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Genome Instability in Health and Disease
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Genome Instability in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 26216

Special Issue Editor

Dr. Kirk McManus

E-Mail Website
Guest Editor
1. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada
2. Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada
Interests: genome instability; chromosome instability; synthetic lethality; micronucleus; ubiquitination/deubiquitination; quantitative imaging microscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A stable genome is a fundamental characteristic of all eukaryotes that is essential for the maintenance and accurate segregation of genetic material in daughter cells. As such, genome stability is vital for normal cell function, physiology, and ultimately species survival. Despite its critical nature, the extensive array of genes, proteins and cellular processes required for genome stability remain poorly understood. Nevertheless, there exist many well characterized processes that are essential for preserving genome stability including DNA repair, DNA replication, centrosome biology, chromatin compaction and chromosome dynamics. Consequently, the aberrant expression, function and regulation of these processes is implicated in disease pathogenesis but is also being explored as a potential therapeutic strategy for disease like cancer.

This Special issue aims to expand our current understanding of genome stability in both physiological and pathological conditions, and on its possible therapeutic exploitation. Experimental studies employing in vitro and in vivo models or review articles are welcome for consideration. As IJMS is a molecular sciences journal, clinical studies will not be considered; however, clinical submissions with biomolecular experiments are welcomed.

Dr. Kirk McManus
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Genome Instability
  • Chromosome Instability
  • DNA Repair
  • DNA Replication
  • Centrosome Biology
  • Chromosome Dynamics
  • Epigenetics, Histone Post-translational Modifications
  • Ubiquitin Dynamics
  • Disease Pathology

Published Papers (7 papers)

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Research

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14 pages, 2542 KiB  
Article
TRIM26 Maintains Cell Survival in Response to Oxidative Stress through Regulating DNA Glycosylase Stability
by Sifaddin M. R. Konis, Jonathan R. Hughes and Jason L. Parsons
Int. J. Mol. Sci. 2022, 23(19), 11613; https://doi.org/10.3390/ijms231911613 - 01 Oct 2022
Cited by 3 | Viewed by 1568
Abstract
Oxidative DNA base lesions in DNA are repaired through the base excision repair (BER) pathway, which consequently plays a vital role in the maintenance of genome integrity and in suppressing mutagenesis. 8-oxoguanine DNA glycosylase (OGG1), endonuclease III-like protein 1 (NTH1), and the endonuclease [...] Read more.
Oxidative DNA base lesions in DNA are repaired through the base excision repair (BER) pathway, which consequently plays a vital role in the maintenance of genome integrity and in suppressing mutagenesis. 8-oxoguanine DNA glycosylase (OGG1), endonuclease III-like protein 1 (NTH1), and the endonuclease VIII-like proteins 1–3 (NEIL1–3) are the key enzymes that initiate repair through the excision of the oxidized base. We have previously identified that the E3 ubiquitin ligase tripartite motif 26 (TRIM26) controls the cellular response to oxidative stress through regulating both NEIL1 and NTH1, although its potential, broader role in BER is unclear. We now show that TRIM26 is a central player in determining the response to different forms of oxidative stress. Using siRNA-mediated knockdowns, we demonstrate that the resistance of cells to X-ray radiation and hydrogen peroxide generated as a consequence of trim26 depletion can be reversed through suppression of selective DNA glycosylases. In particular, a knockdown of neil1 or ogg1 can enhance sensitivity and DNA repair rates in response to X-rays, whereas a knockdown of neil1 or neil3 can produce the same effect in response to hydrogen peroxide. Our study, therefore, highlights the importance of TRIM26 in balancing cellular DNA glycosylase levels required for an efficient BER response. Full article
(This article belongs to the Special Issue Genome Instability in Health and Disease)
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17 pages, 2114 KiB  
Article
Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG
by Pedro Reyes, Benilde García-de Teresa, Ulises Juárez, Fernando Pérez-Villatoro, Moisés O. Fiesco-Roa, Alfredo Rodríguez, Bertha Molina, María Teresa Villarreal-Molina, Jorge Meléndez-Zajgla, Alessandra Carnevale, Leda Torres and Sara Frias
Int. J. Mol. Sci. 2022, 23(4), 2334; https://doi.org/10.3390/ijms23042334 - 20 Feb 2022
Cited by 5 | Viewed by 2700
Abstract
Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases [...] Read more.
Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population. Full article
(This article belongs to the Special Issue Genome Instability in Health and Disease)
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Review

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15 pages, 1487 KiB  
Review
Cytogenetics in Fanconi Anemia: The Importance of Follow-Up and the Search for New Biomarkers of Genomic Instability
by Lismeri Wuicik Merfort, Mateus de Oliveira Lisboa, Luciane Regina Cavalli and Carmem Maria Sales Bonfim
Int. J. Mol. Sci. 2022, 23(22), 14119; https://doi.org/10.3390/ijms232214119 - 15 Nov 2022
Cited by 6 | Viewed by 2416
Abstract
Fanconi Anemia (FA) is a disease characterized by genomic instability, increased sensitivity to DNA cross-linking agents, and the presence of clonal chromosomal abnormalities. This genomic instability can compromise the bone marrow (BM) and confer a high cancer risk to the patients, particularly in [...] Read more.
Fanconi Anemia (FA) is a disease characterized by genomic instability, increased sensitivity to DNA cross-linking agents, and the presence of clonal chromosomal abnormalities. This genomic instability can compromise the bone marrow (BM) and confer a high cancer risk to the patients, particularly in the development of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). The diagnosis of FA patients is complex and cannot be based only on clinical features at presentation. The gold standard diagnostic assay for these patients is cytogenetic analysis, revealing chromosomal breaks induced by DNA cross-linking agents. Clonal chromosome abnormalities, such as the ones involving chromosomes 1q, 3q, and 7, are also common features in FA patients and are associated with progressive BM failure and/or a pre-leukemia condition. In this review, we discuss the cytogenetic methods and their application in diagnosis, stratification of the patients into distinct prognostic groups, and the clinical follow-up of FA patients. These methods have been invaluable for the understanding of FA pathogenesis and identifying novel disease biomarkers. Additional evidence is required to determine the association of these biomarkers with prognosis and cancer risk, and their potential as druggable targets for FA therapy. Full article
(This article belongs to the Special Issue Genome Instability in Health and Disease)
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27 pages, 3172 KiB  
Review
The Role of DNA Repair in Genomic Instability of Multiple Myeloma
by Jana Yasser Hafez Ali, Amira Mohammed Fitieh and Ismail Hassan Ismail
Int. J. Mol. Sci. 2022, 23(10), 5688; https://doi.org/10.3390/ijms23105688 - 19 May 2022
Cited by 3 | Viewed by 2182
Abstract
Multiple Myeloma (MM) is a B cell malignancy marked by genomic instability that arises both through pathogenesis and during disease progression. Despite recent advances in therapy, MM remains incurable. Recently, it has been reported that DNA repair can influence genomic changes and drug [...] Read more.
Multiple Myeloma (MM) is a B cell malignancy marked by genomic instability that arises both through pathogenesis and during disease progression. Despite recent advances in therapy, MM remains incurable. Recently, it has been reported that DNA repair can influence genomic changes and drug resistance in MM. The dysregulation of DNA repair function may provide an alternative explanation for genomic instability observed in MM cells and in cells derived from MM patients. This review provides an overview of DNA repair pathways with a special focus on their involvement in MM and discusses the role they play in MM progression and drug resistance. This review highlights how unrepaired DNA damage due to aberrant DNA repair response in MM exacerbates genomic instability and chromosomal abnormalities, enabling MM progression and drug resistance. Full article
(This article belongs to the Special Issue Genome Instability in Health and Disease)
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34 pages, 3467 KiB  
Review
In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals
by Scott Bachus, Drayson Graves, Lauren Fulham, Nikolas Akkerman, Caelan Stephanson, Jessica Shieh and Peter Pelka
Int. J. Mol. Sci. 2022, 23(7), 4041; https://doi.org/10.3390/ijms23074041 - 06 Apr 2022
Cited by 3 | Viewed by 3346
Abstract
The Never in mitosis gene A (NIMA) family of serine/threonine kinases is a diverse group of protein kinases implicated in a wide variety of cellular processes, including cilia regulation, microtubule dynamics, mitotic processes, cell growth, and DNA damage response. The founding member of [...] Read more.
The Never in mitosis gene A (NIMA) family of serine/threonine kinases is a diverse group of protein kinases implicated in a wide variety of cellular processes, including cilia regulation, microtubule dynamics, mitotic processes, cell growth, and DNA damage response. The founding member of this family was initially identified in Aspergillus and was found to play important roles in mitosis and cell division. The yeast family has one member each, Fin1p in fission yeast and Kin3p in budding yeast, also with functions in mitotic processes, but, overall, these are poorly studied kinases. The mammalian family, the main focus of this review, consists of 11 members named Nek1 to Nek11. With the exception of a few members, the functions of the mammalian Neks are poorly understood but appear to be quite diverse. Like the prototypical NIMA, many members appear to play important roles in mitosis and meiosis, but their functions in the cell go well beyond these well-established activities. In this review, we explore the roles of fungal and mammalian NIMA kinases and highlight the most recent findings in the field. Full article
(This article belongs to the Special Issue Genome Instability in Health and Disease)
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28 pages, 771 KiB  
Review
Therapeutic Targeting of DNA Damage Response in Cancer
by Wonyoung Choi and Eun Sook Lee
Int. J. Mol. Sci. 2022, 23(3), 1701; https://doi.org/10.3390/ijms23031701 - 01 Feb 2022
Cited by 24 | Viewed by 7439
Abstract
DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival [...] Read more.
DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits. Full article
(This article belongs to the Special Issue Genome Instability in Health and Disease)
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19 pages, 2652 KiB  
Review
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability
by Laura L. Thompson, Kailee A. Rutherford, Chloe C. Lepage and Kirk J. McManus
Int. J. Mol. Sci. 2021, 22(16), 8544; https://doi.org/10.3390/ijms22168544 - 09 Aug 2021
Cited by 16 | Viewed by 5428
Abstract
The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation. These SCF complexes are distinguishable by variable F-box proteins, which determine substrate [...] Read more.
The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation. These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. Although the function(s) of each individual SCF complex remain largely unknown, those that have been characterized regulate a wide array of cellular processes, including gene transcription and the cell cycle. In this regard, the SCF complex regulates transcription factors that modulate cell signaling and ensures timely degradation of primary cell cycle regulators for accurate replication and segregation of genetic material. SCF complex members are aberrantly expressed in a myriad of cancer types, with altered expression or function of the invariable core SCF components expected to have a greater impact on cancer pathogenesis than that of the F-box proteins. Accordingly, this review describes the normal roles that various SCF complexes have in maintaining genome stability before discussing the impact that aberrant SCF complex expression and/or function have on cancer pathogenesis. Further characterization of the SCF complex functions is essential to identify and develop therapeutic approaches to exploit aberrant SCF complex expression and function. Full article
(This article belongs to the Special Issue Genome Instability in Health and Disease)
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