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Biomolecules
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DNA Damage Response
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DNA Damage Response

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (26 July 2020) | Viewed by 18600

Special Issue Editors

Dr. Denis Kainov

E-Mail Website
Guest Editor
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7028 Trondheim, Norway
Interests: DNA damage response; DNA repair; DNA damage detection; genotoxic stress; genomic stability; anti-cancer therapy; cell death; apoptosis
Special Issues, Collections and Topics in MDPI journals
Dr. Valentyn Oksenych

E-Mail Website
Co-Guest Editor
1. Department for Cancer Research and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway
2. Department of Biosciences and Nutrition (BioNuT), Karolinska Institutet, 14183 Huddinge, Sweden
3. KG Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway
4. Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway
Interests: DNA repair; DNA damage response; genetics; primary immunodeficiency; B lymphocyte development; mouse models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lesions are generated continuously in our cellular DNA by external and internal factors. The DNA damage response (DDR) detects and repairs the lesions. Failures in DDR results in developmental disorders, innate and adaptive immune responses, cancer, and ageing. We thus invite the submission of original research manuscripts and review articles that cover any aspects of DDR and related topics.

I am looking forward for your contribution.

Dr. Denis Kainov
Dr. Valentyn Oksenych
Guest Editors

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • DNA damage response
  • DNA repair
  • Cell death
  • Genomic instability
  • Innate immunity
  • Adaptive immunity

Published Papers (5 papers)

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Research

26 pages, 5039 KiB  
Article
Regulation of Poly(ADP-Ribose) Polymerase 1 Activity by Y-Box-Binding Protein 1
by Konstantin N. Naumenko, Mariya V. Sukhanova, Loic Hamon, Tatyana A. Kurgina, Elizaveta E. Alemasova, Mikhail M. Kutuzov, David Pastré and Olga I. Lavrik
Biomolecules 2020, 10(9), 1325; https://doi.org/10.3390/biom10091325 - 16 Sep 2020
Cited by 20 | Viewed by 3044
Abstract
Y-box-binding protein 1 (YB-1) is a multifunctional positively charged protein that interacts with DNA or RNA and poly(ADP-ribose) (PAR). YB-1 is poly(ADP-ribosyl)ated and stimulates poly(ADP-ribose) polymerase 1 (PARP1) activity. Here, we studied the mechanism of YB-1-dependent PAR synthesis by PARP1 in vitro using [...] Read more.
Y-box-binding protein 1 (YB-1) is a multifunctional positively charged protein that interacts with DNA or RNA and poly(ADP-ribose) (PAR). YB-1 is poly(ADP-ribosyl)ated and stimulates poly(ADP-ribose) polymerase 1 (PARP1) activity. Here, we studied the mechanism of YB-1-dependent PAR synthesis by PARP1 in vitro using biochemical and atomic force microscopy assays. PAR synthesis activity of PARP1 is known to be facilitated by co-factors such as Mg2+. However, in contrast to an Mg2+-dependent reaction, the activation of PARP1 by YB-1 is accompanied by overall up-regulation of protein PARylation and shortening of the PAR polymer. Therefore, YB-1 and cation co-factors stimulated PAR synthesis in divergent ways. PARP1 autoPARylation in the presence of YB-1 as well as trans-PARylation of YB-1 are greatly affected by the type of damaged DNA, suggesting that PARP1 activation depends on the formation of a PARP1–YB-1–DNA ternary complex. An unstructured C-terminal part of YB-1 involved in an interaction with PAR behaves similarly to full-length YB-1, indicating that both DNA and PAR binding are involved in the stimulation of PARP1 activity by YB-1. Thus, YB-1 is likely linked to the regulation of PARylation events in cells via an interaction with PAR and damaged DNA. Full article
(This article belongs to the Special Issue DNA Damage Response)
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19 pages, 2476 KiB  
Article
EGFP Reporters for Direct and Sensitive Detection of Mutagenic Bypass of DNA Lesions
by Marta Rodriguez-Alvarez, Daria Kim and Andriy Khobta
Biomolecules 2020, 10(6), 902; https://doi.org/10.3390/biom10060902 - 13 Jun 2020
Cited by 2 | Viewed by 3413
Abstract
The sustainment of replication and transcription of damaged DNA is essential for cell survival under genotoxic stress; however, the damage tolerance of these key cellular functions comes at the expense of fidelity. Thus, translesion DNA synthesis (TLS) over damaged nucleotides is a major [...] Read more.
The sustainment of replication and transcription of damaged DNA is essential for cell survival under genotoxic stress; however, the damage tolerance of these key cellular functions comes at the expense of fidelity. Thus, translesion DNA synthesis (TLS) over damaged nucleotides is a major source of point mutations found in cancers; whereas erroneous bypass of damage by RNA polymerases may contribute to cancer and other diseases by driving accumulation of proteins with aberrant structure and function in a process termed “transcriptional mutagenesis” (TM). Here, we aimed at the generation of reporters suited for direct detection of miscoding capacities of defined types of DNA modifications during translesion DNA or RNA synthesis in human cells. We performed a systematic phenotypic screen of 25 non-synonymous base substitutions in a DNA sequence encoding a functionally important region of the enhanced green fluorescent protein (EGFP). This led to the identification of four loss-of-fluorescence mutants, in which any ulterior base substitution at the nucleotide affected by the primary mutation leads to the reversal to a functional EGFP. Finally, we incorporated highly mutagenic abasic DNA lesions at the positions of primary mutations and demonstrated a high sensitivity of detection of the mutagenic DNA TLS and TM in this system. Full article
(This article belongs to the Special Issue DNA Damage Response)
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15 pages, 4471 KiB  
Article
The Human RAD5 Homologs, HLTF and SHPRH, Have Separate Functions in DNA Damage Tolerance Dependent on the DNA Lesion Type
by Mareike Seelinger, Caroline Krogh Søgaard and Marit Otterlei
Biomolecules 2020, 10(3), 463; https://doi.org/10.3390/biom10030463 - 17 Mar 2020
Cited by 4 | Viewed by 3138
Abstract
Helicase-like transcription factor (HLTF) and SNF2, histone-linker, PHD and RING finger domain-containing helicase (SHPRH), the two human homologs of yeast Rad5, are believed to have a vital role in DNA damage tolerance (DDT). Here we show that HLTF, SHPRH and HLTF/SHPRH knockout cell [...] Read more.
Helicase-like transcription factor (HLTF) and SNF2, histone-linker, PHD and RING finger domain-containing helicase (SHPRH), the two human homologs of yeast Rad5, are believed to have a vital role in DNA damage tolerance (DDT). Here we show that HLTF, SHPRH and HLTF/SHPRH knockout cell lines show different sensitivities towards UV-irradiation, methyl methanesulfonate (MMS), cisplatin and mitomycin C (MMC), which are drugs that induce different types of DNA lesions. In general, the HLTF/SHPRH double knockout cell line was less sensitive than the single knockouts in response to all drugs, and interestingly, especially to MMS and cisplatin. Using the SupF assay, we detected an increase in the mutation frequency in HLTF knockout cells both after UV- and MMS-induced DNA lesions, while we detected a decrease in mutation frequency over UV lesions in the HLTF/SHPRH double knockout cells. No change in the mutation frequency was detected in the HLTF/SHPRH double knockout cell line after MMS treatment, even though these cells were more resistant to MMS and grew faster than the other cell lines after treatment with DNA damaging agents. This phenotype could possibly be explained by a reduced activation of checkpoint kinase 2 (CHK2) and MCM2 (a component of the pre-replication complex) after MMS treatment in cells lacking SHPRH. Our data reveal both distinct and common roles of the human RAD5 homologs dependent on the nature of DNA lesions, and identified SHPRH as a regulator of CHK2, a central player in DNA damage response. Full article
(This article belongs to the Special Issue DNA Damage Response)
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12 pages, 1478 KiB  
Article
Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF
by Carole Beck, Sergio Castañeda-Zegarra, Camilla Huse, Mengtan Xing and Valentyn Oksenych
Biomolecules 2020, 10(1), 60; https://doi.org/10.3390/biom10010060 - 30 Dec 2019
Cited by 13 | Viewed by 4014
Abstract
DNA double-strand breaks (DSBs) trigger the Ataxia telangiectasia mutated (ATM)-dependent DNA damage response (DDR), which consists of histone H2AX, MDC1, RNF168, 53BP1, PTIP, RIF1, Rev7, and Shieldin. Early stages of B and T lymphocyte development are dependent on recombination activating gene (RAG)-induced DSBs [...] Read more.
DNA double-strand breaks (DSBs) trigger the Ataxia telangiectasia mutated (ATM)-dependent DNA damage response (DDR), which consists of histone H2AX, MDC1, RNF168, 53BP1, PTIP, RIF1, Rev7, and Shieldin. Early stages of B and T lymphocyte development are dependent on recombination activating gene (RAG)-induced DSBs that form the basis for further V(D)J recombination. Non-homologous end joining (NHEJ) pathway factors recognize, process, and ligate DSBs. Based on numerous loss-of-function studies, DDR factors were thought to be dispensable for the V(D)J recombination. In particular, mice lacking Mediator of DNA Damage Checkpoint Protein 1 (MDC1) possessed nearly wild-type levels of mature B and T lymphocytes in the spleen, thymus, and bone marrow. NHEJ factor XRCC4-like factor (XLF)/Cernunnos is functionally redundant with ATM, histone H2AX, and p53-binding protein 1 (53BP1) during the lymphocyte development in mice. Here, we genetically inactivated MDC1, XLF, or both MDC1 and XLF in murine vAbl pro-B cell lines and, using chromosomally integrated substrates, demonstrated that MDC1 stimulates the V(D)J recombination in cells lacking XLF. Moreover, combined inactivation of MDC1 and XLF in mice resulted in synthetic lethality. Together, these findings suggest that MDC1 and XLF are functionally redundant during the mouse development, in general, and the V(D)J recombination, in particular. Full article
(This article belongs to the Special Issue DNA Damage Response)
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13 pages, 1657 KiB  
Article
Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren
by Sergio Castañeda-Zegarra, Camilla Huse, Øystein Røsand, Antonio Sarno, Mengtan Xing, Raquel Gago-Fuentes, Qindong Zhang, Amin Alirezaylavasani, Julia Werner, Ping Ji, Nina-Beate Liabakk, Wei Wang, Magnar Bjørås and Valentyn Oksenych
Biomolecules 2019, 9(12), 798; https://doi.org/10.3390/biom9120798 - 28 Nov 2019
Cited by 14 | Viewed by 4251
Abstract
Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes, and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. Mutations in several NHEJ genes result in neurological abnormalities and immunodeficiency both in humans and mice. The NHEJ pathway is required [...] Read more.
Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes, and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. Mutations in several NHEJ genes result in neurological abnormalities and immunodeficiency both in humans and mice. The NHEJ pathway is required for V(D)J recombination in developing B and T lymphocytes, and for class switch recombination in mature B cells. The Ku heterodimer formed by Ku70 and Ku80 recognizes DSBs and facilitates the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, Paxx and Mri/Cyren) and downstream core factor subunits X-ray repair cross-complementing group 4 (XRCC4), XRCC4-like factor (XLF), and DNA ligase 4 (Lig4). Accessory factors might be dispensable for the process, depending on the genetic background and DNA lesion type. To determine the physiological role of Mri in DNA repair and development, we introduced a frame-shift mutation in the Mri gene in mice. We then analyzed the development of Mri-deficient mice as well as wild type and immunodeficient controls. Mice lacking Mri possessed reduced levels of class switch recombination in B lymphocytes and slow proliferation of neuronal progenitors when compared to wild type littermates. Human cell lines lacking Mri were as sensitive to DSBs as the wild type controls. Overall, we concluded that Mri/Cyren is largely dispensable for DNA repair and mouse development. Full article
(This article belongs to the Special Issue DNA Damage Response)
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