Next Article in Journal
EBUS-TBNA Cytological Samples for Comprehensive Molecular Testing in Non–Small Cell Lung Cancer
Next Article in Special Issue
Recent Advances in Implantation-Based Genetic Modeling of Biliary Carcinogenesis in Mice
Previous Article in Journal
PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis
Previous Article in Special Issue
Colibactin-Producing Escherichia coli Induce the Formation of Invasive Carcinomas in a Chronic Inflammation-Associated Mouse Model
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 13
Issue 9
10.3390/cancers13092083
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Mouse Models for Deciphering the Impact of Homologous Recombination on Tumorigenesis

by
Gabriel Matos-Rodrigues
1,
Emmanuelle Martini
2,* and
Bernard S. Lopez
1,*
1
Université de Paris, INSERM U1016, UMR 8104 CNRS, Institut Cochin, Equipe, Labellisée Ligue Contre le Cancer, 75014 Paris, France
2
Université de Paris and Université Paris-Saclay, Laboratory of Development of the Gonads, IRCM/IBFJ CEA, Genetic Stability, Stem Cells and Radiation, F-92265 Fontenay aux Roses, France
*
Authors to whom correspondence should be addressed.
Cancers 2021, 13(9), 2083; https://doi.org/10.3390/cancers13092083
Submission received: 7 April 2021 / Revised: 19 April 2021 / Accepted: 20 April 2021 / Published: 25 April 2021
(This article belongs to the Special Issue Carcinogenesis Model)
Browse Figure
Versions Notes

Abstract

:

Simple Summary

Homologous recombination (HR) is a DNA repair pathway essential to genome stability and mutations in many HR genes are correlated with cancer predisposition. Transgenic mouse models are critical to establish HR factors as tumor suppressor genes. However, investigating the effects of suppressing HR genes in vivo is challenging because invalidation of most of them leads to embryonic lethality in mammals. To tackle this issue, elaborated alternative strategies have been developed. Here we review these alternative HR-defective mouse models and reveal the impact of HR defects on tumorigenesis. We highlight that the central HR factor, RAD51, has yet to be well characterized in vivo and, unlike most HR factors, its inactivation has not been associated with cancer predisposition, revealing what we call the “RAD51 paradox”. Finally, we discuss the use of mouse models to develop targeted cancer therapies as well as to understand the mechanisms of HR inactivation-driven tumorigenesis in vivo.

Abstract

Homologous recombination (HR) is a fundamental evolutionarily conserved process that plays prime role(s) in genome stability maintenance through DNA repair and through the protection and resumption of arrested replication forks. Many HR genes are deregulated in cancer cells. Notably, the breast cancer genes BRCA1 and BRCA2, two important HR players, are the most frequently mutated genes in familial breast and ovarian cancer. Transgenic mice constitute powerful tools to unravel the intricate mechanisms controlling tumorigenesis in vivo. However, the genes central to HR are essential in mammals, and their knockout leads to early embryonic lethality in mice. Elaborated strategies have been developed to overcome this difficulty, enabling one to analyze the consequences of HR disruption in vivo. In this review, we first briefly present the molecular mechanisms of HR in mammalian cells to introduce each factor in the HR process. Then, we present the different mouse models of HR invalidation and the consequences of HR inactivation on tumorigenesis. Finally, we discuss the use of mouse models for the development of targeted cancer therapies as well as perspectives on the future potential for understanding the mechanisms of HR inactivation-driven tumorigenesis in vivo.

1. Introduction

Homologous recombination (HR) is a molecular process highly conserved through evolution that plays prominent roles in genome plasticity. Indeed, the DNA repair function(s) and the outcomes of HR are essential not only to maintain genome stability but also to promote genome variability [1,2,3,4,5]. HR allows the repair of different types of DNA lesions, mainly DNA double-strand breaks (DSBs) and interstrand crosslinks (ICLs) [6,7]. Moreover, an important role of HR in genome stability maintenance is the protection and resumption of arrested replication forks. However, prolonged replication fork arrest leads to DSBs that can thus be processed by HR [8,9].
DSBs are generally considered the most toxic lesion. DSBs can be generated by endogenous stresses resulting from cellular metabolism, such as replication stress and reactive oxygen species (ROS), as well as from exogenous factors, such as ionizing radiation and chemotherapy agents (e.g., topoisomerase inhibitors). DSBs can also be programmed to trigger beneficial genomic rearrangements during meiotic differentiation [10] or the establishment of the immune system [11]. HR is also a driving force for the evolution of multigene families [12]. Therefore, thanks to this versatility, HR is involved in many fundamental biological processes. Finally, the technical application of HR constitutes the basis of targeted gene replacement for gene therapy as well as for the precise design of engineered organisms [13,14].
Genetic instability is a hallmark of aging and cancer [15,16,17]. Remarkably, markers of the DNA damage response have been found to be activated at pre-/early steps of tumorigenesis [18,19]. Since replication stress is a prominent endogenous source of DNA damage and genome instability, these data indicate a causal role of DNA replication stress in the early steps of tumor initiation [18,19,20]. Note that genetic instability can also fuel tumor progression. Because of its essential roles in genome stability maintenance, particularly in response to replication stress, HR is generally considered a tumor suppressor mechanism. Indeed, germline and somatic inactivating mutations in major HR actors have been observed in different types of tumors [21]. For example, germline heterozygous mutations in genes directly implicated in HR—BRCA1, BRCA2, PALB2, RAD51C and RAD51D—increase the risk of ovarian and breast cancer [22,23,24,25]. In addition, Fanconi anemia patients with biallelic mutations in BRCA1, BRCA2 and PALB2 show an increased risk of hematological malignancies and solid tumors [26,27,28,29,30,31,32,33].
Mouse models have been powerful tools to address cancer etiology and development in vivo. However, investigations on the effects of HR suppression in vivo have been challenging due to the fact that most HR genes are essential in mammals, and as such, their knockout leads to embryonic lethality. To tackle this issue, elaborated alternative strategies have been developed, and many mouse models have been designed to experimentally address the impact of HR defects on cancer development in vivo.
Here, we first summarize the molecular mechanisms of HR, presenting the roles of the main actors for which mouse models have been designed. Then, we present mouse models of HR deficiency and discuss how they contribute to the understanding of HR-driven tumorigenesis and the development of targeted therapies for HR-inactivated tumors.

2. Molecular Mechanisms of HR

HR-mediated DSB repair represents a paradigm for the molecular steps of HR. DSBs are first recognized and signaled by the MRN complex (MRE11/RAD50/NBS1) in cooperation with the ATM (ataxia-telangiectasia mutated) kinase and the chromatin remodeling machinery. Subsequently, DSBs can be either repaired by canonical nonhomologous end-joining (cNHEJ) or resected (Figure 1A) to then be repaired by HR or other resection-dependent DSB repair processes, such as single strand annealing (SSA) and alternative end-joining [34,35,36]. This choice between NHEJ and resection is controlled by the antagonistic activities of BRCA1, which favors resection, in competition with the protein complex 53BP1-Shieldin (53BP1-REV7-SHLD1-SHLD2-SHLD3), which prevents DNA end resection [37,38,39] (Figure 1A). The steps of HR that succeed DSB recognition can be summarized as follows (Figure 1B): (1) DSB resection to generate a 3′ ssDNA stretch (see Figure 1A); (2) RAD51 loading on the ssDNA, forming the ssDNA-RAD51 filament that promotes a search for homology and invasion of a homologous duplex DNA; (3) DNA synthesis primed by the invading 3′ end; and (4) the formation and resolution of HR intermediates that give rise to gene conversions (nonreciprocal exchange of genetic information) either associated with crossover or not (reciprocal exchange of adjacent sequences) (Figure 1B) (reviewed in [1,3,5]).

2.1. Resection

Resection, which is required to initiate HR, is performed in two steps (Figure 1A). BRCA1 is recruited to DSB sites via its interaction with NBS1 and associates with BARD1, forming an active E3 ubiquitin ligase. This complex ubiquitinates the endonuclease CtIP, which cooperates with MRE11 to initiate DSB resection [40,41]. Then, exonuclease 1 (EXO1) and/or the BLM/DNA2 (helicase/nuclease) complex extend the 3′ overhang [42,43,44,45] (Figure 1B). Finally, the 3′ ssDNA stretch created by resection is coated with replication protein A (RPA), protecting it (Figure 1B).

2.2. Loading RAD51 on ssDNA, Search for Homology and Strand Invasion

The loading of RAD51 onto ssDNA is performed by the BRCA2-PALB2 complex [46,47]. This protein complex interacts with BRCA1 and catalyzes the replacement of RPA by RAD51 on the stretch of 3′ ssDNA, creating the RAD51-ssDNA presynaptic complex [48,49,50]. Note that BRCA1 plays roles during different steps of HR: the initiation of resection and the loading of RAD51 (Figure 1B) [3,51,52].
The ssDNA-RAD51 filament scans the genome to search for homology. Once a homologous sequence is found, the filament invades the duplex homologous DNA and initiates strand exchange, creating a displacement loop (D-loop).

2.3. DNA Synthesis

The 3′ invading strand primes DNA synthesis through the recruitment of DNA and the copy of the invaded DNA molecule. Numerous studies have demonstrated the involvement of many polymerases in this process, although Polδ has been proposed to play a primary role [53]. The protein complexes HROB-MCM8–MCM9 and HELQ are proposed to have redundant helicase functions to promote DNA synthesis during HR [54].

2.4. Formation and Resolution of HR Intermediates

Strand invasion and DNA synthesis lead to the formation of different intermediates whose processing leads to gene conversion either associated with crossover products or not (Figure 1). The invading strand can be disassembled, channeling DSB repair toward synthesis-dependent strand annealing (SDSA) (Figure 1B). If stabilized, the D-loop can lead to DSB repair by break-induced repair (BIR) or to the formation of double Holliday junctions that can be either dissolved by the BLM-TOP3A-RMI1/2 complex or resolved by the structure-specific resolvases MUS81-EME1, GEN1 or SLX1 (Figure 1B) (reviewed in [2,55]).
Of note, the DNA helicase BLM, which is mutated in Bloom syndrome, plays several roles, sometimes contradictory, and at different HR steps. Indeed, BLM is involved in different steps of HR, including end resection at HR initiation [42,56], D-loop rejection and dHJ resolution at HR termination [56,57]. At resection initiation, depending on the cell cycle phase that modifies its interacting partners, BLM either favors the loading of 53BP1 on the DSB in G1 phase, preventing the initiation of unscheduled resection, or, in contrast, favors resection in S phase when interacting with TOP3 [58].

2.5. Accessory Proteins

RAD54, a member of the SWI2/SNF2 protein family (ATP-dependent chromatin remodelers), interacts with RAD51, and in vitro studies have proposed that it functions as a RAD51 cofactor [59,60,61]. RAD54 catalyzes the extension of joint molecules [62] and stabilizes the D-loop [63].
A family of six proteins (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and RAD51AP1), known as the RAD51 paralogs (i.e., proteins that share sequence homology with RAD51 in a given species), has been identified in mammals. Two distinct complexes have been identified: RAD51B–RAD51C–RAD51D–XRCC2 (BCDX2) and RAD51C–XRCC3 (CX3) [64]. RAD51 paralogs favor the recruitment of RAD51 to DNA damage sites [65] and promote the formation and stabilization of the RAD51 nucleoprotein filament. However, the exact role of each paralog remains to be fully determined. In addition, RAD51 paralogs influence gene conversion tract length [66,67]. The SWSAP1 protein, a noncanonical paralog of RAD51, forms the so-called SHU complex when associated with SWS1 (SWSAP1-SWS1). SHU interacts with RAD51 and regulates its function [68].

3. Mouse Models of HR Deficiency

Molecular and cellular studies have detailed the molecular mechanisms of HR and its impact on genome stability maintenance in cultured cells, while clinical human genetic analyses have shown connections between HR defects and cancer development. The disruption of endogenous HR genes in mice should provide an extensive amount of information for understanding not only the molecular mechanisms of HR in vivo but also the etiology of cancer. Such models might constitute useful tools for the development of novel therapies for HR-deficient tumors.

3.1. HR Genes Are Essential in Mammals

Germline ablation of the pivotal HR player Rad51 (see Figure 1B) leads to early embryonic lethality [69,70]. Soon after the discovery of the BRCA genes, many mouse models of germline genetic inactivation of Brca1 and Brca2 were generated using different gene-targeting strategies (Table 1). In all cases, homozygous deletion leads to embryonic lethality [71,72,73,74,75,76,77,78]. Note that homozygous inactivation of BRCA1 and BRCA2 is also proposed to be embryonic lethal in humans [79]. More generally, germline ablation of most other HR genes was also embryonic lethal in mouse models (Table 1).
This evidence from mice and humans suggests that in contrast to other models, such as yeast, zebrafish (Danio rerio) and flies (Drosophila melano), HR is essential in mammals [109,110,111,112]. However, there are a few mammalian HR genes that are not embryonic lethal (Table 2). Importantly, none of these genes control the central steps of HR: loading of RAD51, searching for homology and strand exchange. Based on these phenotypes, we define “essential” HR factors that lead to embryonic lethality when invalidated in mice (Figure 1).

3.2. Partial Loss of HR

To circumvent the embryonic lethality caused by the KO of “essential” HR factors, transgenic mice with partial loss of function of HR genes have been developed. A homozygous frameshift mutation in BRCA1 called BRCA1-AA2800 that creates a truncated protein of 900 amino acids was reported in a patient with breast cancer [126]. Ludwig and colleagues generated a humanized mouse model of BRCA1-AA2800 called Brca1tr. Brca1tr/tr mice showed normal embryonic development and developed a variety of tumors in adulthood, with a high frequency of lymphomas and late onset breast carcinomas/adenomas [127]. This study shows that germline Brca1 mutations can indeed lead to breast cancers without additional concomitant genetic manipulations (e.g., Trp53 inactivation) in mice. However, Brca1tr/tr mice develop a variety of cancers different from those found in BRCA1-AA2800 human carriers.
Similar analyses have been carried out in mouse Brca2 models. In humans, truncating mutations of exon 11 of BRCA2 are associated with ovarian and breast cancer predisposition [128,129,130] (Breast Cancer Information Core, http://research.nhgri.nih.gov/bic/ accessed on 18 April 2021). The exon 11 of BRCA2 codes BRCT domains that are important for its interaction with RAD51 and, therefore, for HR [131,132,133]. Mice carrying truncating mutations of the exon 11 of Brca2 show a high incidence of thymic lymphomas [134,135]. Although the type of tumors observed in humans and mice after disruption of the exon 11 of BRCA2 differ, in both species truncating mutations of the exon 11 of Brca2 is a pro-tumorigenic event.
Many other mouse models of germline partial loss of function of Brca1 and other HR genes have been generated (Table 3), and these studies established the importance of HR for tumor suppression in vivo.

3.3. Genetic Interactions Between HR Factors and other DNA Damage Response and Repair Genes

For most of the “essential” HR genes, including Brca1, Brca2, Rad51, Palb2, Rad51c and Rad51l1/Rad51b, germline co-inactivation of Trp53 delays mouse death for a few days but remains embryonic lethal [70,73,99,103,105].
The knockout of the RAD51 paralog Xrcc2 is an exception in which embryonic lethality occurs at later stages compared to the other “essential” HR genes (Table 1). The double knockout of Xrcc2 and Trp53 rescues embryonic lethality but leads to the development of multiple tumor types, including lymphomas, skin tumors, sarcomas and medulloblastomas, during early adulthood (~10 weeks), illustrating the fact that disrupting HR may induce a broad range of tumors [102].
However, several lines of evidence suggest that specific types of tumors seem to be related to which specific HR gene is affected and how. Using specific transgenic mouse models allowed a different landscape of tumor predisposition to be highlighted, depending on the step at which HR is disrupted. For example, mutations affecting the loading of RAD51 show a strong predisposition to lymphomas, whereas mutation of Brca1, which affects resection, induces a larger type of tumor [88]. Mouse models of Brca2 partial loss of function also show increased tumorigenesis, with a particular predisposition to lymphomas [134,146]. Recently, two independent studies have developed Brca1 mouse models that disrupt the interaction between BRCA1 and PALB2 [141,142]. These mutations abrogate the RAD51-loading function of BRCA1 while maintaining intact BRCA1-dependent control of DSB resection. These mice were born at low frequencies and showed a particular predisposition to the development of lymphomas [141,142]. Therefore, inactivation of Xrcc2, Brca2 or the RAD51-loading function of BRCA1 leads to the formation of different types of tumors compared to Brca1 mouse models that, in addition, abrogate DSB resection, showing that different modes of tumorigenesis exist depending on how HR is invalidated.
The genetic interaction between Brca1 and 53BP1 (Trp53bp1 in mouse) has been uncovered using the Brca1Δ11 mouse model, which lacks exon 11 and therefore does not include a region necessary for the DNA end resection activity of BRCA1 [141,147]. Brca1Δ11 homozygous mice are embryonic lethal, a phenotype that is completely abolished by concomitant Trp53bp1 deletion [147]. The double-inactivated mice present normal HR efficiency and normal development and do not show increased tumorigenesis, highlighting that the rescue of DNA end resection in the Brca1Δ11 mutant by deletion of Trp53bp1 is enough to reverse most phenotypes [147]. In contrast, the Tr53bp1 and Brca1 double knockout mice that are proficient in DNA end resection but defective for RAD51 loading have reduced lifespan, and the mice that survive to adulthood develop lymphomas. As expected, a similar phenotype is found in Brca1 mutants, such as Brca1 L1363P/L1363P and Brca1 CC/CC, which carry mutations affecting the BRCA1-PALB2 interaction and therefore are deficient in RAD51 loading [141,142,148]. Interestingly, Brca1CC/∆11 mice, which carry the combination of two allelic mutations affecting RAD51 loading and DNA end resection, did not develop tumors and had a normal lifespan [141]. Together, these data suggest that the BRCA1-delta11q isoform of BRCA1, which maintains its RAD51 loading activity, provides further evidence that inactivation of BRCA1-mediated RAD51 loading fuels lymphoma development in mice.
The genetic interactions between Brca1 and Tr53bp1 highlight once again that different modes of tumorigenesis are observed depending on the step at which HR is disrupted (Table 4).

3.4. Tissue-Specific Ablation of HR and Targeted Cancer Therapy

Tissue-specific inactivation of HR genes is a powerful tool for in vivo cancer studies. Tissue-specific Brca1 knockout in breast progenitors leads to breast tumor formation [154]. In addition, inactivation of the tumor suppressor Trp53 stimulated tumorigenesis resulting from Brca1 invalidation in mice [155]. Importantly, TP53 mutations are frequently found in BRCA1 tumors [156,157]. Remarkably, Brca1/Trp53 double-inactivated tumors share common histopathological characteristics with human BRCA1 breast cancers, as they are also highly proliferative, estrogen receptor (ER)-negative carcinomas that push borders, express basal epithelial markers, and exhibit a high degree of genomic instability [155]. For these reasons, mouse models with tissue-specific knockout of Brca1 and Trp53 have been extensively used in preclinical investigations [158,159,160,161,162]. Other mouse models have also revealed tumor predisposition upon tissue-specific inactivation of the RAD51 loading factors Palb2 and Brca2 [97,100].
Fanconi anemia patients carrying BRCA2 mutations (FA-D1) also show predisposition to medulloblastoma brain tumors [163,164]. In agreement with a conserved tumor suppressor role of BRCA2 in the brain, Brca2 and Trp53 conditional inactivation in mouse neural progenitors leads to brain tumor formation, including medulloblastoma [165,166]. Curiously, unlike what was seen with BRCA2 loss, Trp53 and Brca1 codepletion in neural progenitors fully rescued the brain phenotypes of Brca1 inactivation alone, and the authors did not report brain tumors [167]. This evidence from tissue-specific knockout of HR factors reinforces the idea that different modes of tumor initiation depend on which step of HR is affected and suggests a special BRCA2 function in the inhibition of brain tumor development. In addition, studies using medulloblastomas derived from the abovementioned Brca2 mouse model pointed to complex genomic rearrangements called chromothripsis as a source of the genetic modifications leading to tumorigenesis in these mice [168].
Poly(ADP-ribose) polymerase (PARP) proteins play important roles during single-strand break repair and participate in the recruitment of the DNA repair machinery after break formation [169,170]. HR-deficient cells are hypersensitive to PARP inhibition, and this characteristic has been explored for potential development of BRCA-/HR-deficient cancer treatments [171,172,173]. Soon after the publication of the synthetic lethality of PARP inhibitors and HR deficiency, Rottenberg and colleagues explored the use of PARP inhibitors for cancer treatment in vivo using a Brca1 mouse model of breast tumors [174]. The authors observed that PARP inhibition decreased tumor growth and increased mouse survival in vivo [174]. Since then, PARP inhibitors have been extensively used in clinical trials, and in 2014, they were approved for maintenance monotherapy in BRCA ovarian tumors that responded to platinum-based treatment [21]. However, acquired resistance is a major issue associated with the use of PARP inhibitors in the clinic [173,174]. PARP inhibitors create selective pressure on new mutations that can restore HR and, thereby, new clones are able to proliferate in the presence of PARP inhibitors and reconstitute tumors [173,175]. Interestingly, Rottenberg and colleagues previously observed such acquired resistance to PARP inhibitors in their mouse models in 2008 [174].
Secondary BRCA mutations restoring HR activity are a common pathway driving resistance to PARP inhibition [173,175]. Recent studies have described additional modes of restoring replication fork stability and/or HR in chemoresistant BRCA cells [173,175,176]. Not surprisingly, BRCA1 and BRCA2 tumors do not develop the same mechanisms of resistance to PARP inhibition [173,175]. Mutations in the 53BP1-sheldin-RIF1-REV7 pathway members generate PARP inhibitor resistance in BRCA1 cells but not BRCA2 cells [177,178,179,180]. Using a Brca2 mouse model of breast tumors, Gogola and colleagues showed that inactivation of poly(ADP-ribose) glycohydrolase (PARG), which catalyzes PARP poly(ADP–ribose) degradation, is another mechanism of acquired resistance to PARP inhibition [181,182]. Therefore, mouse models of HR deficiency are not only important tools for the development of new targeted cancer treatment strategies but can also help elucidate the mechanisms of resistance to therapy.

4. Concluding Remarks and Perspectives

Transgenic mouse models have been key allies in the development and understanding of targeted therapy for HR-deficient tumors. They revealed that HR genes play essential roles in the suppression of tumorigenesis and showed that the modality of tumor predisposition depends on how HR is disrupted. However, to establish a direct relationship between HR disruption and cancer predisposition in vivo, more complex strategies will be necessary. An example that illustrates the limitation of current models is the fact that, in humans, most of the patients with cancer related to BRCA1 and BRCA2 genetic causal variants are heterozygous, while in contrast, Brca1 or Brca2 heterozygous mice are not prone to tumor development.
Despite its pivotal role in HR, the function of the pivotal HR factor RAD51 (see Figure 1B) has yet to be well characterized in vivo. Intriguingly, inactivation of RAD51 has not been associated with cancer predisposition, and the mechanisms behind this “RAD51 paradox” are still unsolved. The only RAD51 mouse model currently in existence is a RAD51 knockout, which is embryonic lethal, limiting our understanding of RAD51 function in vivo. Therefore, the impact of RAD51 on development and tumorigenesis remains to be investigated in vivo. Importantly, this might present a problem for research programs aiming at designing RAD51 inhibitors as therapeutic compounds [183]. Therefore, the development and use of alternative mouse models addressing the role of RAD51 function in vivo should constitute exciting challenges for future research.

Author Contributions

Conceptualization, G.M.-R., E.M. and B.S.L.; writing—original draft preparation, G.M.-R., E.M. and B.S.L.; writing—review and editing, G.M.-R., E.M. and B.S.L.; supervision, E.M. and B.S.L.; funding acquisition, B.S.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ligue Nationale contre le cancer “Equipe labellisée 2020”, ANR (Agence Nationale de la Recherche, ANR-16-CE12-0011-02, and ANR-16-CE18-0012-02), and INCa (Institut National du Cancer, PLBIO18-232). GM-R was supported by a fellowship from “La Ligue nationale contre le Cancer”.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Haber, J.E. Genome Stability. DNA Repair and Recombination, 1st ed.; Garland Science: New York, NY, USA, 2014; ISBN 1317682319. [Google Scholar]
  2. Kowalczykowski, S.C. An overview of the molecular mechanismsof recombinational DNA repair. Cold Spring Harb. Perspect. Biol. 2015, 7, a016410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Jasin, M.; Rothstein, R. Repair of strand breaks by homologous recombination. Cold Spring Harb. Perspect. Biol. 2013, 5, a012740. [Google Scholar] [CrossRef]
  4. Piazza, A.; Heyer, W.D. Homologous Recombination and the Formation of Complex Genomic Rearrangements. Trends Cell Biol. 2019, 29, 135–149. [Google Scholar] [CrossRef] [PubMed]
  5. Wright, W.D.; Shah, S.S.; Heyer, W.D. Homologous recombination and the repair of DNA double-strand breaks. J. Biol. Chem. 2018, 293, 10524–10535. [Google Scholar] [CrossRef] [Green Version]
  6. Deans, A.J.; West, S.C. DNA interstrand crosslink repair and cancer. Nat. Rev. Cancer 2011, 11, 467–480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Chen, C.-C.; Feng, W.; Lim, P.X.; Kass, E.M.; Jasin, M. Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer. Annu. Rev. Cancer Biol. 2018, 2, 313–336. [Google Scholar] [CrossRef]
  8. Petermann, E.; Orta, M.L.; Issaeva, N.; Schultz, N.; Helleday, T. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol. Cell 2010, 37, 492–502. [Google Scholar] [CrossRef] [Green Version]
  9. Saintigny, Y.; Delacote, F.; Vares, G.; Petitot, F.; Lambert, S.; Averbeck, D.; Lopez, B.S. Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J. 2001, 20, 3861–3870. [Google Scholar] [CrossRef] [PubMed]
  10. Hunter, N. Meiotic recombination: The essence of heredity. Cold Spring Harb. Perspect. Biol. 2015, 7, a016618. [Google Scholar] [CrossRef] [Green Version]
  11. Jung, D.; Alt, F.W. Unraveling V(D)J recombination; insights into gene regulation. Cell 2004, 116, 299–311. [Google Scholar] [CrossRef] [Green Version]
  12. Guirouilh-Barbat, J.; Lambert, S.; Bertrand, P.; Lopez, B.S. Is homologous recombination really an error-free process? Front. Genet. 2014, 5, 175. [Google Scholar] [CrossRef] [Green Version]
  13. Rocha-Martins, M.; Cavalheiro, G.R.; Matos-Rodrigues, G.E.; Martins, R.A.P. From gene targeting to genome editing: Transgenic animals applications and beyond. An. Acad. Bras. Cienc. 2015, 87, 1323–1348. [Google Scholar] [CrossRef]
  14. Gaj, T.; Gersbach, C.A.; Barbas, C.F. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 2013, 31, 397–405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Negrini, S.; Gorgoulis, V.G.; Halazonetis, T.D. Genomic instability—An evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 2010, 11, 220–228. [Google Scholar] [CrossRef]
  16. López-Otín, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell 2013, 153, 1194–1217. [Google Scholar] [CrossRef] [Green Version]
  17. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Bartkova, J.; Horejsi, Z.; Koed, K.; Kramer, A.; Tort, F.; Zieger, K.; Guldberg, P.; Sehested, M.; Nesland, J.M.; Lukas, C.; et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 2005, 434, 864–870. [Google Scholar] [CrossRef] [PubMed]
  19. Gorgoulis, V.G.; Vassiliou, L.V.; Karakaidos, P.; Zacharatos, P.; Kotsinas, A.; Liloglou, T.; Venere, M.; Ditullio, R.A.J.; Kastrinakis, N.G.; Levy, B.; et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 2005, 434, 907–913. [Google Scholar] [CrossRef]
  20. Tubbs, A.; Nussenzweig, A. Endogenous DNA Damage as a Source of Genomic Instability in Cancer. Cell 2017, 168, 644–656. [Google Scholar] [CrossRef] [Green Version]
  21. Lord, C.J.; Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 2016, 16, 110–120. [Google Scholar] [CrossRef] [PubMed]
  22. Kuchenbaecker, K.B.; Hopper, J.L.; Barnes, D.R.; Phillips, K.; Mooij, T.M.; Jervis, S.; Van Leeuwen, F.E.; Milne, R.L.; Andrieu, N.; Goldgar, D.E.; et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for. JAMA 2017, 317, 2402–2416. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Antoniou, A.C.; Casadei, S.; Heikkinen, T.; Barrowdale, D.; Pylkäs, K.; Roberts, J.; Lee, A.; Subramanian, D.; De Leeneer, K.; Fostira, F.; et al. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med. 2014, 371, 497–506. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Coulet, F.; Fajac, A.; Colas, C.; Eyries, M.; Dion-Minière, A.; Rouzier, R.; Uzan, S.; Lefranc, J.P.; Carbonnel, M.; Cornelis, F.; et al. Germline RAD51C mutations in ovarian cancer susceptibility. Clin. Genet. 2013, 83, 332–336. [Google Scholar] [CrossRef]
  25. Ducy, M.; Sesma-Sanz, L.; Guitton-Sert, L.; Lashgari, A.; Gao, Y.; Brahiti, N.; Rodrigue, A.; Margaillan, G.; Caron, M.C.; Côté, J.; et al. The Tumor Suppressor PALB2: Inside Out. Trends Biochem. Sci. 2019, 44, 226–240. [Google Scholar] [CrossRef] [PubMed]
  26. Kee, Y.; D’Andrea, A.D. Molecular pathogenesis and clinical management of Fanconi anemia. J. Clin. Investig. 2012, 122, 3799–3806. [Google Scholar] [CrossRef] [Green Version]
  27. Domchek, S.M.; Tang, J.; Stopfer, J.; Lilli, D.R.; Hamel, N.; Tischkowitz, M.; Monteiro, A.N.A.; Messick, T.E.; Powers, J.; Yonker, A.; et al. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov. 2013, 3, 399–405. [Google Scholar] [CrossRef] [Green Version]
  28. Sawyer, S.L.; Tian, L.; Kähkönen, M.; Schwartzentruber, J.; Kircher, M.; Majewski, J.; Dyment, D.A.; Innes, A.M.; Boycott, K.M.; Moreau, L.A.; et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov. 2015, 5, 135–142. [Google Scholar] [CrossRef] [Green Version]
  29. Freire, B.L.; Homma, T.K.; Funari, M.F.A.; Lerario, A.M.; Leal, A.M.; Velloso, E.D.R.P.; Malaquias, A.C.; Jorge, A.A.L. Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients. Eur. J. Med. Genet. 2018, 61, 130–133. [Google Scholar] [CrossRef]
  30. Niraj, J.; Färkkilä, A.; D’Andrea, A.D. The Fanconi Anemia Pathway in Cancer. Annu. Rev. Cancer Biol. 2019, 3, 457–478. [Google Scholar] [CrossRef]
  31. Howlett, N.G.; Taniguchi, T.; Olson, S.; Cox, B.; Waisfisz, Q.; De Die-Smulders, C.; Persky, N.; Grompe, M.; Joenje, H.; Pals, G.; et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002, 297, 606–609. [Google Scholar] [CrossRef]
  32. Seo, A.; Orna, S.S.; Unal, S.; Casadei, S.; Walsh, T.; Gumruk, F.; Shalev, S.; Shimamura, A.; Akarsu, N.A.; Tamary, H.; et al. Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1. Proc. Natl. Acad. Sci. USA 2018, 115, 5241–5246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Auerbach, A.D. Fanconi anemia and its diagnosis. Mutat. Res. 2009, 668, 4–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Rass, E.; Grabarz, A.; Plo, I.; Gautier, J.; Bertrand, P.; Lopez, B.S.B.S. Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat. Struct. Mol. Biol. 2009, 16, 819–824. [Google Scholar] [CrossRef] [PubMed]
  35. Betermier, M.; Bertrand, P.; Lopez, B.S.B.S.; Bétermier, M.; Bertrand, P.; Lopez, B.S.B.S. Is Non-Homologous End-Joining Really an Inherently Error-Prone Process? PLoS Genet. 2014, 10, e1004086. [Google Scholar] [CrossRef] [Green Version]
  36. So, A.; Le Guen, T.; Lopez, B.S.B.S.; Guirouilh-Barbat, J. Genomic rearrangements induced by unscheduled DNA double strand breaks in somatic mammalian cells. FEBS J. 2017, 284, 2324–2344. [Google Scholar] [CrossRef] [Green Version]
  37. Mirman, Z.; de Lange, T. 53BP1: A DSB escort. Genes Dev. 2020, 34, 7–23. [Google Scholar] [CrossRef] [Green Version]
  38. Setiaputra, D.; Durocher, D. Shieldin—The protector of DNA ends. EMBO Rep. 2019, 20, e47560. [Google Scholar] [CrossRef]
  39. Tarsounas, M.; Sung, P. The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication. Nat. Rev. Mol. Cell Biol. 2020, 21, 284–299. [Google Scholar] [CrossRef] [PubMed]
  40. Yu, X.; Fu, S.; Lai, M.; Baer, R.; Chen, J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 2006, 20, 1721–1726. [Google Scholar] [CrossRef]
  41. Sartori, A.A.; Lukas, C.; Coates, J.; Mistrik, M.; Fu, S.; Bartek, J.; Baer, R.; Lukas, J.; Jackson, S.P. Human CtIP promotes DNA end resection. Nature 2007, 450, 509–514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Nimonkar, A.V.; Genschel, J.; Kinoshita, E.; Polaczek, P.; Campbell, J.L.; Wyman, C.; Modrich, P.; Kowalczykowski, S.C. BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev. 2011, 25, 350–362. [Google Scholar] [CrossRef] [Green Version]
  43. Mimitou, E.P.; Symington, L.S. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 2008, 455, 770–774. [Google Scholar] [CrossRef] [Green Version]
  44. Zhu, Z.; Chung, W.H.; Shim, E.Y.; Lee, S.E.; Ira, G. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 2008, 134, 981–994. [Google Scholar] [CrossRef] [Green Version]
  45. Cejka, P.; Cannavo, E.; Polaczek, P.; Masuda-Sasa, T.; Pokharel, S.; Campbell, J.L.; Kowalczykowski, S.C. DNA end resection by Dna2-Sgs1-RPA and its stimulation by Top3-Rmi1 and Mre11-Rad50-Xrs2. Nature 2010, 467, 112–116. [Google Scholar] [CrossRef] [PubMed]
  46. Jensen, R.B.; Carreira, A.; Kowalczykowski, S.C. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 2010, 467, 678–683. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Thorslund, T.; McIlwraith, M.J.; Compton, S.A.; Lekomtsev, S.; Petronczki, M.; Griffith, J.D.; West, S.C. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 2010, 17, 1263–1265. [Google Scholar] [CrossRef] [PubMed]
  48. Xia, B.; Sheng, Q.; Nakanishi, K.; Ohashi, A.; Wu, J.; Christ, N.; Liu, X.; Jasin, M.; Couch, F.J.; Livingston, D.M. Control of BRCA2 Cellular and Clinical Functions by a Nuclear Partner, PALB2. Mol. Cell 2006, 22, 719–729. [Google Scholar] [CrossRef] [PubMed]
  49. Sy, S.M.H.; Huen, M.S.Y.; Chen, J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc. Natl. Acad. Sci. USA 2009, 106, 7155–7160. [Google Scholar] [CrossRef] [Green Version]
  50. Zhang, F.; Ma, J.; Wu, J.; Ye, L.; Cai, H.; Xia, B.; Yu, X. PALB2 Links BRCA1 and BRCA2 in the DNA-Damage Response. Curr. Biol. 2009, 19, 524–529. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Zhao, W.; Wiese, C.; Kwon, Y.; Hromas, R.; Sung, P. The BRCA tumor suppressor network in chromosome damage repair by homologous recombination. Annu. Rev. Biochem. 2019, 88, 221–245. [Google Scholar] [CrossRef]
  52. Moynahan, M.E.; Chiu, J.W.; Koller, B.H.; Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 1999, 4, 511–518. [Google Scholar] [CrossRef]
  53. McVey, M.; Khodaverdian, V.Y.; Meyer, D.; Cerqueira, P.G.; Heyer, W.-D. Eukaryotic DNA Polymerases in Homologous Recombination. Annu. Rev. Genet. 2016, 50, 393–421. [Google Scholar] [CrossRef] [Green Version]
  54. Hustedt, N.; Saito, Y.; Zimmermann, M.; Álvarez-Quilón, A.; Setiaputra, D.; Adam, S.; McEwan, A.; Yuan, J.Y.; Olivieri, M.; Zhao, Y.; et al. Control of homologous recombination by the HROB-MCM8-MCM9 pathway. Genes Dev. 2019, 33, 1397–1415. [Google Scholar] [CrossRef] [PubMed]
  55. Bizard, A.H.; Hickson, I.D. The dissolution of double Holliday junctions. Cold Spring Harb. Perspect. Biol. 2014, 6, a016477. [Google Scholar] [CrossRef] [PubMed]
  56. Chu, W.K.; Hanada, K.; Kanaar, R.; Hickson, I.D. BLM has early and late functions in homologous recombination repair in mouse embryonic stem cells. Oncogene 2010, 29, 4705–4714. [Google Scholar] [CrossRef] [Green Version]
  57. Larsen, N.B.; Hickson, I.D. RecQ helicases: Conserved guardians of genomic integrity. Adv. Exp. Med. Biol. 2013, 767, 161–184. [Google Scholar]
  58. Grabarz, A.; Guirouilh-Barbat, J.J.; Barascu, A.A.; Pennarun, G.G.; Genet, D.; Rass, E.; Germann, S.M.S.M.S.M.; Bertrand, P.; Hickson, I.D.I.D.I.D.; Lopez, B.S.B.S. A role for BLM in double-strand break repair pathway choice: Prevention of CtIP/Mre11-mediated alternative nonhomologous end-joining. Cell Rep. 2013, 5, 21–28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Mazin, A.V.; Bornarth, C.J.; Solinger, J.A.; Heyer, W.D.; Kowalczykowski, S.C. Rad54 protein is targeted to pairing loci by the Rad51 nucleoprotein filament. Mol. Cell 2000, 6, 583–592. [Google Scholar] [CrossRef]
  60. Crickard, J.B.; Moevus, C.J.; Kwon, Y.; Sung, P.; Greene, E.C. Rad54 Drives ATP Hydrolysis-Dependent DNA Sequence Alignment during Homologous Recombination. Cell 2020, 181, 1380–1394.e18. [Google Scholar] [CrossRef]
  61. Sigurdsson, S.; Van Komen, S.; Petukhova, G.; Sung, P. Homologous DNA pairing by human recombination factors Rad51 and Rad54. J. Biol. Chem. 2002, 277, 42790–42794. [Google Scholar] [CrossRef] [Green Version]
  62. Bugreev, D.V.; Hanaoka, F.; Mazin, A.V. Rad54 dissociates homologous recombination intermediates by branch migration. Nat. Struct. Mol. Biol. 2007, 14, 746–753. [Google Scholar] [CrossRef] [PubMed]
  63. Wright, W.D.; Heyer, W.D. Rad54 Functions as a Heteroduplex DNA Pump Modulated by Its DNA Substrates and Rad51 during D Loop Formation. Mol. Cell 2014, 53, 420–432. [Google Scholar] [CrossRef] [Green Version]
  64. Masson, J.Y.; Tarsounas, M.C.; Stasiak, A.Z.; Stasiak, A.; Shah, R.; McIlwraith, M.J.; Benson, F.E.; West, S.C. Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev. 2001, 15, 3296–3307. [Google Scholar] [CrossRef] [Green Version]
  65. Garcin, E.B.; Gon, S.; Sullivan, M.R.; Brunette, G.J.; de Cian, A.; Concordet, J.P.; Giovannangeli, C.; Dirks, W.G.; Eberth, S.; Bernstein, K.A.; et al. Differential requirements for the RAD51 paralogs in genome repair and maintenance in human cells. PLoS Genet. 2019, 15, e1008355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Nagaraju, G.; Odate, S.; Xie, A.; Scully, R. Differential Regulation of Short- and Long-Tract Gene Conversion between Sister Chromatids by Rad51C. Mol. Cell. Biol. 2006, 26, 8075–8086. [Google Scholar] [CrossRef] [Green Version]
  67. Nagaraju, G.; Hartlerode, A.; Kwok, A.; Chandramouly, G.; Scully, R. XRCC2 and XRCC3 Regulate the Balance between Short- and Long-Tract Gene Conversions between Sister Chromatids. Mol. Cell. Biol. 2009, 29, 4283–4294. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Sullivan, M.R.; Bernstein, K.A. RAD-ical new insights into RAD51 regulation. Genes 2018, 9, 629. [Google Scholar] [CrossRef] [Green Version]
  69. Tsuzuki, T.; Fujii, Y.; Sakumi, K.; Tominaga, Y.; Nakao, K.; Sekiguchi, M.; Matsushiro, A.; Yoshimura, Y.; Morita, T. Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc. Natl. Acad. Sci. USA 1996, 93, 6236–6240. [Google Scholar] [CrossRef] [Green Version]
  70. Lim, D.S.; Hasty, P. A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53. Mol. Cell. Biol. 1996, 16, 7133–7143. [Google Scholar] [CrossRef] [Green Version]
  71. Hakem, R.; de la Pompa, J.L.; Sirard, C.; Mo, R.; Woo, M.; Hakem, A.; Wakeham, A.; Potter, J.; Reitmair, A.; Billia, F.; et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 1996, 85, 1009–1023. [Google Scholar] [CrossRef] [Green Version]
  72. Liu, C.Y.; Flesken-Nikitin, A.; Li, S.; Zeng, Y.; Lee, W.H. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 1996, 10, 1835–1843. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Ludwig, T.; Chapman, D.L.; Papaioannou, V.E.; Efstratiadis, A. Targeted mutations of breast cancer susceptibility gene homologs in mice: Lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 1997, 11, 1226–1241. [Google Scholar] [CrossRef] [Green Version]
  74. Gowen, L.C.; Johnson, B.L.; Latour, A.M.; Sulik, K.K.; Koller, B.H. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat. Genet. 1996, 12, 191–194. [Google Scholar] [CrossRef]
  75. Shen, S.X.; Weaver, Z.; Xu, X.; Li, C.; Weinstein, M.; Chen, L.; Guan, X.Y.; Ried, T.; Deng, C.X. A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability. Oncogene 1998, 17, 3115–3124. [Google Scholar] [CrossRef] [Green Version]
  76. Bennett, L.M.; McAllister, K.A.; Blackshear, P.E.; Malphurs, J.; Goulding, G.; Collins, N.K.; Ward, T.; Bunch, D.O.; Eddy, E.M.; Davis, B.J.; et al. Brca2-null embryonic survival is prolonged on the balb/c genetics background. Mol. Carcinog. 2000, 28, 174–183. [Google Scholar] [CrossRef]
  77. Stambolic, V.; Suzuki, A.; de la Pompa, J.L.; Brothers, G.M.; Mirtsos, C.; Sasaki, T.; Ruland, J.; Penninger, J.M.; Siderovski, D.P.; Mak, T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998, 95, 29–39. [Google Scholar] [CrossRef] [Green Version]
  78. Sharan, S.K.; Morimatsu, M.; Albrecht, U.; Lim, D.S.; Regel, E.; Dinh, C.; Sands, A.; Eichele, G.; Hasty, P.; Bradley, A. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 [see comments]. Nature 1997, 386, 804–810. [Google Scholar] [CrossRef]
  79. Judkins, T.; Hendrickson, B.C.; Deffenbaugh, A.M.; Eliason, K.; Leclair, B.; Norton, M.J.; Ward, B.E.; Pruss, D.; Scholl, T. Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. Cancer Res. 2005, 65, 10096–10103. [Google Scholar] [CrossRef] [Green Version]
  80. Buis, J.; Wu, Y.; Deng, Y.; Leddon, J.; Westfield, G.; Eckersdorff, M.; Sekiguchi, J.M.; Chang, S.; Ferguson, D.O. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 2008, 135, 85–96. [Google Scholar] [CrossRef] [Green Version]
  81. Luo, G.; Yao, M.S.; Bender, C.F.; Mills, M.; Bladl, A.R.; Bradley, A.; Petrini, J.H.J. Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc. Natl. Acad. Sci. USA 1999, 96, 7376–7381. [Google Scholar] [CrossRef] [Green Version]
  82. Zhu, J.; Petersen, S.; Tessarollo, L.; Nussenzweig, A. Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr. Biol. 2001, 11, 105–109. [Google Scholar] [CrossRef] [Green Version]
  83. Dumon-Jones, V.; Frappart, P.O.; Tong, W.M.; Sajithlal, G.; Hulla, W.; Schmid, G.; Herceg, Z.; Digweed, M.; Wang, Z.Q. Nbn Heterozygosity Renders Mice Susceptible to Tumor Formation and Ionizing Radiation-Induced Tumorigenesis. Cancer Res. 2003, 63, 7263–7269. [Google Scholar]
  84. Demuth, I.; Frappart, P.O.; Hildebrand, G.; Melchers, A.; Lobitz, S.; Stöckl, L.; Varon, R.; Herceg, Z.; Sperling, K.; Wang, Z.Q.; et al. An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability. Hum. Mol. Genet. 2004, 13, 2385–2397. [Google Scholar] [CrossRef] [PubMed]
  85. Chen, P.-L.; Liu, F.; Cai, S.; Lin, X.; Li, A.; Chen, Y.; Gu, B.; Lee, E.Y.-H.P.; Lee, W.-H. Inactivation of CtIP Leads to Early Embryonic Lethality Mediated by G1 Restraint and to Tumorigenesis by Haploid Insufficiency. Mol. Cell. Biol. 2005, 25, 3535–3542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Lin, W.; Sampathi, S.; Dai, H.; Liu, C.; Zhou, M.; Hu, J.; Huang, Q.; Campbell, J.; Shin-Ya, K.; Zheng, L.; et al. Mammalian DNA2 helicase/nuclease cleaves G-quadruplex DNA and is required for telomere integrity. EMBO J. 2013, 32, 1425–1439. [Google Scholar] [CrossRef] [Green Version]
  87. Chester, N.; Kuo, F.; Kozak, C.; O’Hara, C.D.; Leder, P. Stage-specific apoptosis, developmental delay, and embryonic lethality in mice homozygous for a targeted disruption in the murine Bloom’s syndrome gene. Genes Dev. 1998, 12, 3382–3393. [Google Scholar] [CrossRef] [Green Version]
  88. Xu, X.; Qiao, W.; Linke, S.P.; Cao, L.; Li, W.M.; Furth, P.A.; Harris, C.C.; Deng, C.X. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat. Genet. 2001, 28, 266–271. [Google Scholar] [CrossRef]
  89. Hohenstein, P.; Kielman, M.F.; Breukel, C.; Bennett, L.M.; Wiseman, R.; Krimpenfort, P.; Cornelisse, C.; Van Ommen, G.J.; Devilee, P.; Fodde, R. A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage. Oncogene 2001, 20, 2544–2550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Shakya, R.; Szabolcs, M.; McCarthy, E.; Ospina, E.; Basso, K.; Nandula, S.; Murty, V.; Baer, R.; Ludwig, T. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc. Natl. Acad. Sci. USA 2008, 105, 7040–7045. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Drost, R.; Bouwman, P.; Jonkers, J. BRCA1 185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1 The Journal of Clinical Investigation. J. Clin. Investig. 2016, 126, 2903–2918. [Google Scholar] [CrossRef]
  92. Drost, R.; Bouwman, P.; Rottenberg, S.; Boon, U.; Schut, E.; Klarenbeek, S.; Klijn, C.; van der Heijden, I.; van der Gulden, H.; Wientjens, E.; et al. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell 2011, 20, 797–809. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Nacson, J.; Krais, J.J.; Bernhardy, A.J.; Clausen, E.; Feng, W.; Wang, Y.; Nicolas, E.; Cai, K.Q.; Tricarico, R.; Hua, X.; et al. BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance. Cell Rep. 2018, 24, 3513–3527.e7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Suzuki, A.; De La Pompa, J.L.; Hakem, R.; Elia, A.; Yoshida, R.; Mo, K.; Nishina, H.; Chuang, T.; Wakeham, A.; Itie, A.; et al. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 1997, 11, 1242–1252. [Google Scholar] [CrossRef] [Green Version]
  95. Yan, D.H.; Wen, Y.; Su, L.K.; Xia, W.; Wang, S.C.; Zhang, S.; Gan, L.; Lee, D.F.; Spohn, B.; Frey, J.A.; et al. A delayed chemically induced tumorigenesis in Brca2 mutant mice. Oncogene 2004, 23, 1896–1901. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Morimatsu, M.; Donoho, G.; Hasty, P. Cells deleted for Brca2 COOH terminus exhibit hypersensitivity to γ- radiation and premature senescence. Cancer Res. 1998, 58, 3441–3447. [Google Scholar]
  97. Jonkers, J.; Meuwissen, R.; Van der Gulden, H.; Peterse, H.; Van der Valk, M.; Berns, A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 2001, 29, 418–425. [Google Scholar] [CrossRef]
  98. Rantakari, P.; Nikkilä, J.; Jokela, H.; Ola, R.; Pylkäs, K.; Lagerbohm, H.; Sainio, K.; Poutanen, M.; Winqvist, R. Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice. Hum. Mol. Genet. 2010, 19, 3021–3029. [Google Scholar] [CrossRef] [Green Version]
  99. Bouwman, P.; Drost, R.; Klijn, C.; Pieterse, M.; Van Der Gulden, H.; Song, J.Y.; Szuhai, K.; Jonkers, J. Loss of p53 partially rescues embryonic development of Palb2 knockout mice but does not foster haploinsufficiency of Palb2 in tumour suppression. J. Pathol. 2011, 224, 10–21. [Google Scholar] [CrossRef]
  100. Bowman-Colin, C.; Xia, B.; Bunting, S.; Klijn, C.; Drost, R.; Bouwman, P.; Fineman, L.; Chen, X.; Culhane, A.C.; Cai, H.; et al. Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 8632–8637. [Google Scholar] [CrossRef] [Green Version]
  101. Deans, B.; Griffin, C.S.; Maconochie, M.; Thacker, J. Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. EMBO J. 2000, 19, 6675–6685. [Google Scholar] [CrossRef]
  102. Orii, K.E.; Lee, Y.; Kondo, N.; McKinnon, P.J. Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. Proc. Natl. Acad. Sci. USA 2006, 103, 10017–10022. [Google Scholar] [CrossRef] [Green Version]
  103. Shu, Z.; Smith, S.; Wang, L.; Rice, M.C.; Kmiec, E.B. Disruption of muREC2/RAD51L1 in Mice Results in Early Embryonic Lethality Which Can Be Partially Rescued in a p53−/− Background. Mol. Cell. Biol. 1999, 19, 8686–8693. [Google Scholar] [CrossRef] [Green Version]
  104. Smeenk, G.; de Groot, A.J.L.; Romeijn, R.J.; van Buul, P.P.W.; Zdzienicka, M.Z.; Mullenders, L.H.F.; Pastink, A.; Godthelp, B.C. Rad51C is essential for embryonic development and haploinsufficiency causes increased DNA damage sensitivity and genomic instability. Mutat. Res. Fundam. Mol. Mech. Mutagen. 2010, 689, 50–58. [Google Scholar] [CrossRef] [PubMed]
  105. Kuznetsov, S.G.; Haines, D.C.; Martin, B.K.; Sharan, S.K. Loss of Rad51c leads to embryonic lethality and modulation of Trp53-dependent tumorigenesis in mice. Cancer Res. 2009, 69, 863–872. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Pittman, D.L.; Schimenti, J.C. Midgestation lethality in mice deficient for the RecA-related gene, Rad51d/Rad51l3. Genesis 2000, 26, 167–173. [Google Scholar] [CrossRef]
  107. Uchimura, A.; Hidaka, Y.; Hirabayashi, T.; Hirabayashi, M.; Yagi, T. DNA polymerase δ is required for early mammalian embryogenesis. PLoS ONE 2009, 4, e4183. [Google Scholar] [CrossRef] [Green Version]
  108. Li, W.; Wang, J.C. Mammalian DNA topoisomerase IIIα is essential in early embryogenesis. Proc. Natl. Acad. Sci. USA 1998, 95, 1010–1013. [Google Scholar] [CrossRef] [Green Version]
  109. Game, J.C.; Mortimer, R.K. A genetic study of x-ray sensitive mutants in yeast. Mutat. Res. 1974, 24, 281–292. [Google Scholar] [CrossRef]
  110. Karpenshif, Y.; Bernstein, K.A. From yeast to mammals: Recent advances in genetic control of homologous recombination. DNA Repair 2012, 11, 781–788. [Google Scholar] [CrossRef] [Green Version]
  111. Botthof, J.G.; Bielczyk-Maczynska, E.; Ferreira, L.; Cvejic, A. Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish. Proc. Natl. Acad. Sci. USA 2017, 114, E4452–E4461. [Google Scholar] [CrossRef] [Green Version]
  112. Staeva-Vieira, E.; Yoo, S.; Lehmann, R. An essential role of DmRad51/SpnA in DNA repair and meiotic checkpoint control. EMBO J. 2003, 22, 5863–5874. [Google Scholar] [CrossRef] [Green Version]
  113. Wei, K.; Clark, A.B.; Wong, E.; Kane, M.F.; Mazur, D.J.; Parris, T.; Kolas, N.K.; Russell, R.; Hou, H.; Kneitz, B.; et al. Inactivation of exonuclease I in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. Genes Dev. 2003, 17, 603–614. [Google Scholar] [CrossRef] [Green Version]
  114. Essers, J.; Hendriks, R.W.; Swagemakers, S.M.; Troelstra, C.; de Wit, J.; Bootsma, D.; Hoeijmakers, J.H.; Kanaar, R. Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell 1997, 89, 195–204. [Google Scholar] [CrossRef] [Green Version]
  115. Abreu, C.M.; Prakash, R.; Romanienko, P.J.; Roig, I.; Keeney, S.; Jasin, M. Shu complex SWS1-SWSAP1 promotes early steps in mouse meiotic recombination. Nat. Commun. 2018, 9, 3961. [Google Scholar] [CrossRef] [Green Version]
  116. Lutzmann, M.; Grey, C.; Traver, S.; Ganier, O.; Maya-Mendoza, A.; Ranisavljevic, N.; Bernex, F.; Nishiyama, A.; Montel, N.; Gavois, E.; et al. MCM8- and MCM9-Deficient Mice Reveal Gametogenesis Defects and Genome Instability Due to Impaired Homologous Recombination. Mol. Cell 2012, 47, 523–534. [Google Scholar] [CrossRef] [Green Version]
  117. Lutzmann, M.; Bernex, F.; da Costa de Jesus, C.; Hodroj, D.; Marty, C.; Plo, I.; Vainchenker, W.; Tosolini, M.; Forichon, L.; Bret, C.; et al. MCM8- and MCM9 Deficiencies Cause Lifelong Increased Hematopoietic DNA Damage Driving p53-Dependent Myeloid Tumors. Cell Rep. 2019, 28, 2851–2865.e4. [Google Scholar] [CrossRef] [PubMed]
  118. Adelman, C.A.; Lolo, R.L.; Birkbak, N.J.; Murina, O.; Matsuzaki, K.; Horejsi, Z.; Parmar, K.; Borel, V.; Skehel, J.M.; Stamp, G.; et al. HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis. Nature 2013, 502, 381–384. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. McPherson, J.P.; Lemmers, B.; Chahwan, R.; Pamidi, A.; Migon, E.; Matysiak-Zablocki, E.; Moynahan, M.E.; Essers, J.; Hanada, K.; Poonepalli, A.; et al. Involvement of mammalian Mus81 in genome integrity and tumor suppression. Science 2004, 304, 1822–1826. [Google Scholar] [CrossRef] [PubMed]
  120. Dendouga, N.; Gao, H.; Moechars, D.; Janicot, M.; Vialard, J.; McGowan, C.H. Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis. Mol. Cell. Biol. 2005, 25, 7569–7579. [Google Scholar] [CrossRef] [Green Version]
  121. Wang, X.; Wang, H.; Guo, B.; Zhang, Y.; Gong, Y.; Zhang, C.; Xu, H.; Wu, X. Gen1 and Eme1 Play Redundant Roles in DNA Repair and Meiotic Recombination in Mice. DNA Cell Biol. 2016, 35, 585–590. [Google Scholar] [CrossRef] [PubMed]
  122. Castor, D.; Nair, N.; Déclais, A.-C.; Lachaud, C.; Toth, R.; Macartney, T.J.; Lilley, D.M.J.; Arthur, J.S.C.; Rouse, J. Cooperative control of holliday junction resolution and DNA repair by the SLX1 and MUS81-EME1 nucleases. Mol. Cell 2013, 52, 221–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Wang, H.; Zhang, C.; Wang, X.; Lian, Y.; Guo, B.; Han, M.; Zhang, X.; Zhu, X.; Xu, S.; Guo, Z.; et al. Disruption of gen1 causes congenital anomalies of the kidney and urinary tract in mice. Int. J. Biol. Sci. 2018, 14, 10–20. [Google Scholar] [CrossRef] [Green Version]
  124. Crossan, G.P.; Van Der Weyden, L.; Rosado, I.V.; Langevin, F.; Gaillard, P.H.L.; McIntyre, R.E.; Gallagher, F.; Kettunen, M.I.; Lewis, D.Y.; Brindle, K.; et al. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nat. Genet. 2011, 43, 147–152. [Google Scholar] [CrossRef] [Green Version]
  125. Hodskinson, M.R.G.; Silhan, J.; Crossan, G.P.; Garaycoechea, J.I.; Mukherjee, S.; Johnson, C.M.; Schärer, O.D.; Patel, K.J. Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair. Mol. Cell 2014, 54, 472–484. [Google Scholar] [CrossRef] [Green Version]
  126. Boyd, M.; Harris, F.; McFarlane, R.; Davidson, H.R.; Black, D.M. A human brca1 gene knockout. Nature 1995, 375, 541–542. [Google Scholar] [CrossRef] [PubMed]
  127. Ludwig, T.; Fisher, P.; Ganesan, S.; Efstratiadis, A. Tumorigenesis in mice carrying a truncating Brca1 mutation. Genes Dev. 2001, 15, 1188–1193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Thompson, D.; Easton, D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am. J. Hum. Genet. 2001, 68, 410–419. [Google Scholar] [CrossRef] [Green Version]
  129. Gayther, S.A.; Mangion, J.; Russell, P.; Seal, S.; Barfoot, R.; Ponder, B.A.J.; Stratton, M.R.; Easton, D. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat. Genet. 1997, 15, 103–105. [Google Scholar] [CrossRef] [PubMed]
  130. Labidi-Galy, S.I.; Olivier, T.; Rodrigues, M.; Ferraioli, D.; Derbel, O.; Bodmer, A.; Petignat, P.; Rak, B.; Chopin, N.; Tredan, O.; et al. Location of mutation in BRCA2 gene and survival in patients with ovarian cancer. Clin. Cancer Res. 2018, 24, 326–333. [Google Scholar] [CrossRef] [Green Version]
  131. Wong, A.K.; Pero, R.; Ormonde, P.A.; Tavtigian, S.V.; Bartel, P.L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J. Biol. Chem. 1997, 272, 31941–31944. [Google Scholar] [CrossRef] [Green Version]
  132. Carreira, A.; Hilario, J.; Amitani, I.; Baskin, R.J.; Shivji, M.K.K.; Venkitaraman, A.R.; Kowalczykowski, S.C. The BRC Repeats of BRCA2 Modulate the DNA-Binding Selectivity of RAD51. Cell 2009, 136, 1032–1043. [Google Scholar] [CrossRef] [Green Version]
  133. Carreira, A.; Kowalczykowski, S.C. Two classes of BRC repeats in BRCA2 promote RAD51 nucleoprotein filament function by distinct mechanisms. Proc. Natl. Acad. Sci. USA 2011, 108, 10448–10453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Friedman, L.S.; Thistlethwaite, F.C.; Patel, K.J.; Yu, V.P.C.C.; Lee, H.; Venkitaraman, A.R.; Abel, K.J.; Carlton, M.B.L.; Hunter, S.M.; Colledge, W.H.; et al. Thymic lymphomas in mice with a truncating mutation in BRCA2. Cancer Res. 1998, 58, 1338–1343. [Google Scholar] [PubMed]
  135. Connor, F.; Bertwistle, D.; Joseph Mee, P.; Ross, G.M.; Swift, S.; Grigorieva, E.; Tybulewicz, V.L.J.; Ashworth, A. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat. Genet. 1997, 17, 423–431. [Google Scholar] [CrossRef] [PubMed]
  136. Kim, S.S.; Cao, L.; Lim, S.-C.; Li, C.; Wang, R.-H.; Xu, X.; Bachelier, R.; Deng, C.-X. Hyperplasia and Spontaneous Tumor Development in the Gynecologic System in Mice Lacking the BRCA1-Δ11 Isoform. Mol. Cell. Biol. 2006, 26, 6983–6992. [Google Scholar] [CrossRef] [Green Version]
  137. Shakya, R.; Reid, L.J.; Reczek, C.R.; Cole, F.; Egli, D.; Lin, C.S.; DeRooij, D.G.; Hirsch, S.; Ravi, K.; Hicks, J.B.; et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 2011, 334, 525–528. [Google Scholar] [CrossRef] [Green Version]
  138. Reid, L.J.; Shakya, R.; Modi, A.P.; Lokshin, M.; Cheng, J.T.; Jasin, M.; Baer, R.; Ludwig, T. E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks. Proc. Natl. Acad. Sci. USA 2008, 105, 20876–20881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Kim, S.S.; Cao, L.; Li, C.; Xu, X.; Huber, L.J.; Chodosh, L.A.; Deng, C.-X. Uterus Hyperplasia and Increased Carcinogen-Induced Tumorigenesis in Mice Carrying a Targeted Mutation of the Chk2 Phosphorylation Site in Brca1. Mol. Cell. Biol. 2004, 24, 9498–9507. [Google Scholar] [CrossRef] [Green Version]
  140. Kim, S.S.; Cao, L.; Baek, H.J.; Lim, S.C.; Li, C.; Wang, R.H.; Xu, X.; Cho, K.H.; Deng, C.X. Impaired skin and mammary gland development and increased γ-irradiation-induced tumorigenesis in mice carrying a mutation of S1152-ATM phosphorylation site in Brca1. Cancer Res. 2009, 69, 9291–9300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Nacson, J.; Di Marcantonio, D.; Wang, Y.; Sykes, S.M.; Johnson, N.; Nacson, J.; Hua, X.; Wang, Y.; Bernhardy, A.J.; Clausen, E.; et al. BRCA1 Mutational Complementation Induces Synthetic Viability Short Article BRCA1 Mutational Complementation Induces Synthetic Viability. Mol. Cell 2020, 78, 1–9. [Google Scholar] [CrossRef]
  142. Park, D.; Bergin, S.M.; Jones, D.; Ru, P.; Koivisto, C.S.; Jeon, Y.-J.; Sizemore, G.M.; Kladney, R.D.; Hadjis, A.; Shakya, R.; et al. Ablation of the Brca1-Palb2 interaction phenocopies Fanconi anemia in mice. Cancer Res. 2020, 80, 4172–4180. [Google Scholar] [CrossRef]
  143. Hartford, S.A.; Chittela, R.; Ding, X.; Vyas, A.; Martin, B.; Burkett, S.; Haines, D.C.; Southon, E.; Tessarollo, L.; Sharan, S.K. Interaction with PALB2 Is Essential for Maintenance of Genomic Integrity by BRCA2. PLoS Genet. 2016, 12, e1006236. [Google Scholar] [CrossRef] [PubMed]
  144. McAllister, K.A.; Bennett, L.M.; Houle, C.D.; Ward, T.; Malphurs, J.; Collins, N.K.; Cachafeiro, C.; Haseman, J.; Goulding, E.H.; Bunch, D.; et al. Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res. 2002, 62, 990–994. [Google Scholar]
  145. Simhadri, S.; Peterson, S.; Patel, D.S.; Huo, Y.; Cai, H.; Bowman-Colin, C.; Miller, S.; Ludwig, T.; Ganesan, S.; Bhaumik, M.; et al. Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice. J. Biol. Chem. 2014, 289, 24617–24629. [Google Scholar] [CrossRef] [Green Version]
  146. O’Connor, L.; Strasser, A.; O’Reilly, L.A.; Hausmann, G.; Adams, J.M.; Cory, S.; Huang, D.C. Bim: A novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 1998, 17, 384–395. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Cao, L.; Xu, X.; Bunting, S.F.; Liu, J.; Wang, R.H.; Cao, L.L.; Wu, J.J.; Peng, T.N.; Chen, J.; Nussenzweig, A.; et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol. Cell 2009, 35, 534–541. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Chen, J.; Li, P.; Song, L.; Bai, L.; Huen, M.S.Y.; Liu, Y.; Lu, L.Y. 53BP1 loss rescues embryonic lethality but not genomic instability of BRCA1 total knockout mice. Cell Death Differ. 2020, 27, 2552–2567. [Google Scholar] [CrossRef] [Green Version]
  149. Cao, L.; Kim, S.; Xiao, C.; Wang, R.H.; Coumoul, X.; Wang, X.; Wen, M.L.; Xia, L.X.; De Soto, J.A.; Takai, H.; et al. ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. EMBO J. 2006, 25, 2167–2177. [Google Scholar] [CrossRef] [Green Version]
  150. Zong, D.; Adam, S.; Wang, Y.; Sasanuma, H.; Callén, E.; Murga, M.; Day, A.; Kruhlak, M.J.; Wong, N.; Munro, M.; et al. BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation. Mol. Cell 2019, 73, 1267–1281.e7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  151. Callen, E.; Zong, D.; Wu, W.; Wong, N.; Stanlie, A.; Ishikawa, M.; Pavani, R.; Dumitrache, L.C.; Byrum, A.K.; Mendez-Dorantes, C.; et al. 53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. Mol. Cell 2020, 77, 26–38.e7. [Google Scholar] [CrossRef]
  152. Bunting, S.F.; Callén, E.; Kozak, M.L.; Kim, J.M.; Wong, N.; López-Contreras, A.J.; Ludwig, T.; Baer, R.; Faryabi, R.B.; Malhowski, A.; et al. BRCA1 Functions Independently of Homologous Recombination in DNA Interstrand Crosslink Repair. Mol. Cell 2012, 46, 125–135. [Google Scholar] [CrossRef] [Green Version]
  153. McAllister, K.A.; Houle, C.D.; Malphurs, J.; Ward, T.; Collins, N.K.; Gersch, W.; Wharey, L.; Seely, J.C.; Betz, L.; Bennett, L.M.; et al. Spontaneous and irradiation-induced tumor susceptibility in Brca2 germline mutant mice and cooperative effects with a p53 germline mutation. Toxicol. Pathol. 2006, 34, 187–198. [Google Scholar] [CrossRef] [PubMed]
  154. Xu, X.; Wagner, K.U.; Larson, D.; Weaver, Z.; Li, C.; Ried, T.; Hennighausen, L.; Wynshaw-Boris, A.; Deng, C.X. Conditional mutation of Brca 1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat. Genet. 1999, 22, 37–43. [Google Scholar] [CrossRef] [PubMed]
  155. Liu, X.; Holstege, H.; Van Der Gulden, H.; Treur-Mulder, M.; Zevenhoven, J.; Velds, A.; Kerkhoven, R.M.; Van Vliet, M.H.; Wessels, L.F.A.; Petersen, J.L.; et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 12111–12116. [Google Scholar] [CrossRef] [Green Version]
  156. Greenblatt, M.S.; Chappuis, P.O.; Bond, J.P.; Hamel, N.; Foulkes, W.D. TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: Distinctive spectrum and structural distribution. Cancer Res. 2001, 61, 4092–4097. [Google Scholar] [PubMed]
  157. Rhei, E.; Bogomolniy, F.; Federici, M.G.; Maresco, D.L.; Offit, K.; Robson, M.E.; Saigo, P.E.; Boyd, J. Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers. Cancer Res. 1998, 58, 3193–3196. [Google Scholar] [PubMed]
  158. Dine, J.; Deng, C.-X.X. Mouse models of BRCA1 and their application to breast cancer research. Cancer Metastasis Rev. 2013, 32, 25–37. [Google Scholar] [CrossRef]
  159. Drost, R.M.; Jonkers, J. Preclinical mouse models for BRCA1-associated breast cancer. Br. J. Cancer 2009, 101, 1651–1657. [Google Scholar] [CrossRef] [PubMed]
  160. Puppe, J.; Opdam, M.; Schouten, P.C.; Jozwiak, K.; Lips, E.; Severson, T.; van de Ven, M.; Brambillasca, C.; Bouwman, P.; van Tellingen, O.; et al. EZH2 is overexpressed in BRCA1-like breast tumors and predictive for sensitivity to high-dose platinum-based chemotherapy. Clin. Cancer Res. 2019, 25, 4351–4362. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  161. van de Ven, M.; Liu, X.; van der Burg, E.; Klarenbeek, S.; Alexi, X.; Zwart, W.; Dijcks, F.; Bouwman, P.; Jonkers, J. BRCA1-associated mammary tumorigenesis is dependent on estrogen rather than progesterone signaling. J. Pathol. 2018, 246, 41–53. [Google Scholar] [CrossRef]
  162. Kersten, K.; Visser, K.E.; Miltenburg, M.H.; Jonkers, J. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol. Med. 2017, 9, 137–153. [Google Scholar] [CrossRef] [PubMed]
  163. Offit, K.; Levran, O.; Mullaney, B.; Mah, K.; Nafa, K.; Batish, S.D.; Diotti, R.; Scheider, H.; Deffenbaugh, A.; Scholl, T.; et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J. Natl. Cancer Inst. 2003, 95, 1548–1551. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Hirsch, B.; Shimamura, A.; Moreau, L.; Baldinger, S.; Hag-Alshiekh, M.; Bostrom, B.; Sencer, S.; D’Andrea, A.D. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood 2004, 103, 2554–2559. [Google Scholar] [CrossRef] [Green Version]
  165. Frappart, P.-O.; Lee, Y.; Lamont, J.; McKinnon, P.J. BRCA2 is required for neurogenesis and suppression of medulloblastoma. EMBO J. 2007, 26, 2732–2742. [Google Scholar] [CrossRef] [PubMed]
  166. Frappart, P.O.; Lee, Y.; Russell, H.R.; Chalhoub, N.; Wang, Y.D.; Orii, K.E.; Zhao, J.; Kondo, N.; Baker, S.J.; McKinnon, P.J. Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc. Natl. Acad. Sci. USA 2009, 106, 1880–1885. [Google Scholar] [CrossRef] [Green Version]
  167. Pao, G.M.; Zhu, Q.; Perez-Garcia, C.G.; Chou, S.J.; Suh, H.; Gage, F.H.; O’Leary, D.D.M.; Verma, I.M. Role of BRCA1 in brain development. Proc. Natl. Acad. Sci. USA 2014, 111, E1240–E1248. [Google Scholar] [CrossRef] [Green Version]
  168. Ratnaparkhe, M.; Wong, J.K.L.; Wei, P.C.; Hlevnjak, M.; Kolb, T.; Simovic, M.; Haag, D.; Paul, Y.; Devens, F.; Northcott, P.; et al. Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. Nat. Commun. 2018, 9, 4760. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Gupte, R.; Liu, Z.; Kraus, W.L. Parps and adp-ribosylation: Recent advances linking molecular functions to biological outcomes. Genes Dev. 2017, 31, 101–126. [Google Scholar] [CrossRef] [Green Version]
  170. O’Sullivan, J.; Tedim Ferreira, M.; Gagné, J.P.; Sharma, A.K.; Hendzel, M.J.; Masson, J.Y.; Poirier, G.G. Emerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation. Nat. Commun. 2019, 10, 1182. [Google Scholar] [CrossRef] [Green Version]
  171. Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434, 913–917. [Google Scholar] [CrossRef]
  172. Farmer, H.; McCabe, N.; Lord, C.J.; Tutt, A.N.; Johnson, D.A.; Richardson, T.B.; Santarosa, M.; Dillon, K.J.; Hickson, I.; Knights, C.; et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005, 434, 917–921. [Google Scholar] [CrossRef]
  173. Noordermeer, S.M.; van Attikum, H. PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells. Trends Cell Biol. 2019, 29, 820–834. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Rottenberg, S.; Jaspers, J.E.; Kersbergen, A.; Van Der Burg, E.; Nygren, A.O.H.; Zander, S.A.L.; Derksen, P.W.B.; De Bruin, M.; Zevenhoven, J.; Lau, A.; et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. USA 2008, 105, 17079–17084. [Google Scholar] [CrossRef] [Green Version]
  175. Gogola, E.; Rottenberg, S.; Jonkers, J. Resistance to PARP Inhibitors: Lessons from Preclinical Models of BRCA-Associated Cancer. Annu. Rev. Cancer Biol. 2019, 3, 235–254. [Google Scholar] [CrossRef]
  176. Chaudhuri, A.R.; Callen, E.; Ding, X.; Gogola, E.; Duarte, A.A.; Lee, J.E.; Wong, N.; Lafarga, V.; Calvo, J.A.; Panzarino, N.J.; et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 2016, 535, 382–387. [Google Scholar] [CrossRef]
  177. Bunting, S.F.; Callen, E.; Wong, N.; Chen, H.T.; Polato, F.; Gunn, A.; Bothmer, A.; Feldhahn, N.; Fernandez-Capetillo, O.; Cao, L.; et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 2010, 141, 243–254. [Google Scholar] [CrossRef] [Green Version]
  178. Noordermeer, S.M.; Adam, S.; Setiaputra, D.; Barazas, M.; Pettitt, S.J.; Ling, A.K.; Olivieri, M.; Álvarez-Quilón, A.; Moatti, N.; Zimmermann, M.; et al. The shieldin complex mediates 53BP1-dependent DNA repair. Nature 2018, 560, 117–121. [Google Scholar] [CrossRef]
  179. Chapman, J.R.; Barral, P.; Vannier, J.B.; Borel, V.; Steger, M.; Tomas-Loba, A.; Sartori, A.A.; Adams, I.R.; Batista, F.D.; Boulton, S.J. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol. Cell 2013, 49, 858–871. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  180. Bouwman, P.; Aly, A.; Escandell, J.M.; Pieterse, M.; Bartkova, J.; van der Gulden, H.; Hiddingh, S.; Thanasoula, M.; Kulkarni, A.; Yang, Q.; et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 2010, 17, 688–695. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  181. Gogola, E.; Duarte, A.A.; de Ruiter, J.R.; Wiegant, W.W.; Schmid, J.A.; de Bruijn, R.; James, D.I.; Guerrero Llobet, S.; Vis, D.J.; Annunziato, S.; et al. Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality. Cancer Cell 2018, 33, 1078–1093.e12. [Google Scholar] [CrossRef] [Green Version]
  182. Kassab, M.A.; Yu, L.L.; Yu, X. Targeting dePARylation for cancer therapy. Cell Biosci. 2020, 10. [Google Scholar] [CrossRef] [PubMed]
  183. Grundy, M.K.; Buckanovich, R.J.; Bernstein, K.A. Regulation and pharmacological targeting of RAD51 in cancer. NAR Cancer 2020. [Google Scholar] [CrossRef] [PubMed]
Cancers 13 02083 g001 550
Figure 1. HR-mediated DSB repair. (A). Signaling and competition between cNHEJ and resection [34]. The involvement of 53BP1, BRCA1 and the MRN complex. (B). Model of DSB repair by HR. (1) The MRN complex initiates a 5′ to 3′ resection under the control of BRCA1/CtIP, generating a 3′ single-stranded DNA (ssDNA) (A). (2) RAD51 is then loaded to the 3′ single-stranded DNA by the combined action of BRCA2/PALB2 and BRCA1, resulting in the formation of an ordered RAD51-ssDNA nucleofilament. The invasion of homologous duplex DNA by the RAD51-ssDNA filament induces the formation of a displacement loop (D-loop). (3) The invading strand primes DNA synthesis. (4) The D-loop can be either dismantled, leading to DSB repair by synthesis-dependent strand annealing (SDSA) or stabilized, leading to either DSB repair by BIR or the formation of a double Holliday junction (dHJ). The dHJ can be resolved or dissolved, leading to a repair product either associated with a crossover event or not. The proteins involved in each corresponding step are listed on the right side of the figure. Light gray circles indicate essential factors; essential factors are defined as genes whose knockout leads to embryonic lethality in mice. Dark gray circles indicate nonessential factors; these are genes whose KO does not lead to embryonic lethality in mice.
Figure 1. HR-mediated DSB repair. (A). Signaling and competition between cNHEJ and resection [34]. The involvement of 53BP1, BRCA1 and the MRN complex. (B). Model of DSB repair by HR. (1) The MRN complex initiates a 5′ to 3′ resection under the control of BRCA1/CtIP, generating a 3′ single-stranded DNA (ssDNA) (A). (2) RAD51 is then loaded to the 3′ single-stranded DNA by the combined action of BRCA2/PALB2 and BRCA1, resulting in the formation of an ordered RAD51-ssDNA nucleofilament. The invasion of homologous duplex DNA by the RAD51-ssDNA filament induces the formation of a displacement loop (D-loop). (3) The invading strand primes DNA synthesis. (4) The D-loop can be either dismantled, leading to DSB repair by synthesis-dependent strand annealing (SDSA) or stabilized, leading to either DSB repair by BIR or the formation of a double Holliday junction (dHJ). The dHJ can be resolved or dissolved, leading to a repair product either associated with a crossover event or not. The proteins involved in each corresponding step are listed on the right side of the figure. Light gray circles indicate essential factors; essential factors are defined as genes whose knockout leads to embryonic lethality in mice. Dark gray circles indicate nonessential factors; these are genes whose KO does not lead to embryonic lethality in mice.
Cancers 13 02083 g001
Table
Table 1. Embryonic lethal mouse models of complete or severe loss of function of HR genes. Phenotype: when the mutant allele is in homozygosis. EL: embryonic lethal. N/A: not available. “Enumber”: day of embryonic development death.
Table 1. Embryonic lethal mouse models of complete or severe loss of function of HR genes. Phenotype: when the mutant allele is in homozygosis. EL: embryonic lethal. N/A: not available. “Enumber”: day of embryonic development death.
GeneAllelePhenotypeReference
Mre11Mre11Δ5N/A[80]
Rad50Rad50Δ1–2EL: E7[81]
Nbs1/NbnNbs1ex1EL: E3-7[82]
Nbs1/NbnNbs1ex6EL: E3-7[83]
Nbs1/NbnNbs1Δ6EL: N/A[84]
CtIP/Rbbp8CtIPneoEL: E3-7[85]
Dna2Dna24–7EL: E7[86]
BlmBlmneoEL: E10-14[87]
Brca1Brca15–6EL: E6-7[71]
Brca1Brca1koEL: E6-7[72]
Brca1Brca1ex2EL: E6-7[73]
Brca1Brca1223–763EL: E8-13[74]
Brca1Brca1−11EL: E8[75]
Brca1Brca1in10ex11EL: E9[88]
Brca1Brca1700TEL: E10[89]
Brca1Brca1Δ11EL: E12-18[88]
Brca1Brca1Δ2N/A[90]
Brca1Brca1185stopEL: E10-13[91]
Brca1BRCA15382stopEL: E9-12[91]
Brca1Brca1C61GEL: E12[92]
Brca1Brca1ΔCEL: E9[93]
Brca2Brca2−10–11EL: E8-10[76,94]
Brca2Brca2Brdm1EL: E7-8[78]
Brca2Brca2ex11EL: E8[73]
Brca2Brca21593N-terEL: E8-9[95]
Brca2Brca2lex2N/A[96]
Brca2Brca2Δ11EL: E8[97]
Palb2Palb2GTEL: E8-9[98,99]
Palb2Palb2Δ2–3EL: E8-10[100]
Rad51Rad51ex5EL: Prior to E8[69]
Rad51Rad51M1EL: E7-8[70]
Xrcc2Xrcc2ex3EL: E12-18[101]
Xrcc2Xrcc2Δ3N/A[102]
Rad51b/Rad51l1Rad51bβ-geoEL: E8[103]
Rad51cRad51c-spliceEL: E8-10[104]
Rad51cRad51Δ2–3EL: E8[105]
Rad51d/Rad51l3Rad51dex4–6EL: E8-11[106]
Xrcc3N/A
Pold1Pold1koEL: E4-E7[107]
Top3aTop3aex6EL: prior to E7[108]
Table
Table 2. Nonembryonic lethal mouse models of complete or severe loss of function of HR genes. Phenotype: when the mutant allele is in homozygosis. N/A: not available.
Table 2. Nonembryonic lethal mouse models of complete or severe loss of function of HR genes. Phenotype: when the mutant allele is in homozygosis. N/A: not available.
GeneAllelePhenotypeReference
Exo1Exo1hygLifespan reduction and increased cancer susceptibility[113]
Rad54Rad54307neoNo somatic phenotype[114]
Sws1Sws1∆1(A)No somatic phenotype[115]
Swsap1Swsap1∆131No somatic phenotype[115]
Mcm8Mcm8Δ11–12Late onset myeloid tumors[116,117]
Mcm9Mcm9Δ1–2Late onset myeloid tumors[116,117]
HrobHrobfsN/A[54]
HelQHelQΔcIncreased cancer susceptibility[118]
Mus81Mux81ex3–5Lifespan reduction and increased cancer susceptibility (lymphoma)[119]
Mus81Mus81Δ9–12No somatic phenotype[120]
Eme1Gen1PBN/A[121]
Slx1Slx1Δ1No somatic phenotype[122]
Gen1Gen1PBFrequently developed kidney and urinary tract defects[123]
Slx4/Btbd12Slx4koMice are born in sub-Mendelian ratios and show reduced lifespan and increased cancer susceptibility[124,125]
Table
Table 3. Mouse models of partial loss of function of HR genes. Phenotype in homozygotes.
Table 3. Mouse models of partial loss of function of HR genes. Phenotype in homozygotes.
GeneAllelePhenotypeReference
Brca1Brca1trDevelop a variety of tumors: lymphomas, sarcomas and carcinomas/adenomas, including breast carcinomas/adenomas.[127]
Brca1Brca1flAdult mice present hyperplasia in the gynecologic system, thymic lymphoma and mammary gland hyperplasia with very dense branches and hyperplasic and/or neoplastic foci.[136]
Brca1Brca1SFIncreased tumor incidence[137]
Brca1Brca1FH-I26ANormal development, no increased tumor incidence[137,138]
Brca1Brca1S971AFemales develop uterus hyperplasia and ovarian abnormalities by 2 years of age.[139]
Brca1Brca1S1152ASome mice exhibit aging-like phenotypes, including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis. Aging-unaffected 18-month-old females show mammary gland abnormalities.[140]
Brca1Brca1ccApproximately 15% of the expected number of embryos reach birth. The mice who survive until adulthood show developmental features of Fanconi anemia and T cell acute lymphoblastic leukemia.[141]
Brca1Brca1lpMice are born in the expected Mendelian frequency. These mice show developmental features of Fanconi anemia and T-lymphoblastic lymphoma/leukemia.[142]
Brca2Brca2tm1CamMice are born in sub-Mendelian ratios. The extent of embryonic lethality is dependent on the genetic background. The mice who survive until adulthood presented multiple developmental and growth defects, in addition to the development of thymic lymphomas between 12 and 14 weeks of age.[134]
Brca2Brca2Tr2014Mice are born in sub-Mendelian ratios. The extent of embryonic lethality is dependent on the genetic background. The mice who survive until adulthood presented multiple developmental and growth defects, in addition to the development of thymic lymphomas.[135]
Brca2Brca2G25RIncreased B-cell lymphoma and other cancer types in aged mice.[143]
Brca2Brca2Δ27Mice are born in sub-Mendelian ratios. The mice that survive until adulthood show an increased incidence of a variety of tumors, including carcinomas, adenomas, lymphomas, and sarcomas.[144]
Palb2Palb2cc6No somatic phenotype.[145]
Table
Table 4. Mouse models of genetic inactivation of HR genes with other DNA repair and DNA damage response genes. Phenotype: when the mutant allele is in homozygosis.
Table 4. Mouse models of genetic inactivation of HR genes with other DNA repair and DNA damage response genes. Phenotype: when the mutant allele is in homozygosis.
GeneHR-Mutated AlleleAdditional Genetic ModificationPhenotypeReference
Brca1Brca1Δ11Trp53+/−Rescue the embryonic lethality. Most female mice present mammary tumors, these mice also present lymphomas and ovarian tumors.[88]
Brca1Brca1Δ11Trp53−/−Rescue the embryonic lethality. No further characterization.[88]
Brca1Brca1Δ11Cdkn1a−/−No rescue of embryonic lethality[88]
Brca1Brca1Δ11Bax−/−No rescue of embryonic lethality[88]
Brca1Brca1Δ11Atm−/−Rescue the embryonic lethality. No further characterization.[149]
Brca1Brca1Δ11Chk2−/−Rescue the embryonic lethality. These mice present features of premature aging, including decreased skin thickness, kyphosis, decreased bone density and intestinal villi atrophy. In addition, mice exhibit enhanced cancer prevalence, including mammary and ovary tumors in high frequency.[149]
Brca1Brca1lpTrp53−/−Rescue of bone marrow failure, but not growth defects. These mice show increased frequency of T-lymphoblastic lymphoma/leukemia[142]
Brca1Brca1Δ11Trp53bp1−/−Rescue of embryonic lethality. No increased tumor incidence or features of premature aging.[147]
Brca1Brca1Δ11H2ax−/−No rescue of embryonic lethality.[150]
Brca1Brca1Δ11Rnf168−/−No rescue of embryonic lethality.[150]
Brca1Brca1Δ11Rnf8−/−No rescue of embryonic lethality.[150]
Brca1Brca1Δ11Trp53bp1S25ARescue of embryonic lethality. Features of premature aging and decreased lifespan.[151]
Brca1Brca1Δ11Ku80−/−No rescue of embryonic lethality[152]
Brca1Brca1ex2Trp53bp1−/−Pups were obtained at a frequency slightly lower than the expected Mendelian ratio.[152]
Brca1Brca1ΔCTrp53bp1−/−Rescue of embryonic lethality. These mice develop thymic lymphomas between 3-6 months of age.[141]
Brca1Brca1Δ5–13Trp53bp1−/−Partial rescue of embryonic lethality. These mice develop thymic lymphoma within 7 months[148]
Brca2Brca2Δ27Trp53+/−Decrease in lifespan and increase in tumor prevalence.[153]
Brca2Brca2G25RTrp53+/−Enhanced tumor prevalence.[143]
Palb2Palb2cc6Rnf168−/−Embryonic lethal.[150]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Matos-Rodrigues, G.; Martini, E.; Lopez, B.S. Mouse Models for Deciphering the Impact of Homologous Recombination on Tumorigenesis. Cancers 2021, 13, 2083. https://doi.org/10.3390/cancers13092083

AMA Style

Matos-Rodrigues G, Martini E, Lopez BS. Mouse Models for Deciphering the Impact of Homologous Recombination on Tumorigenesis. Cancers. 2021; 13(9):2083. https://doi.org/10.3390/cancers13092083

Chicago/Turabian Style

Matos-Rodrigues, Gabriel, Emmanuelle Martini, and Bernard S. Lopez. 2021. "Mouse Models for Deciphering the Impact of Homologous Recombination on Tumorigenesis" Cancers 13, no. 9: 2083. https://doi.org/10.3390/cancers13092083

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop