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Endogenous DNA Damage and Repair
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Endogenous DNA Damage and Repair

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 December 2023) | Viewed by 12434

Special Issue Editors

Prof. Dr. David M Wilson III

E-Mail Website
Guest Editor
Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Interests: oxidative DNA damage; DNA repair mechanisms; neurodegenerative disease
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Bruce Demple

E-Mail Website
Guest Editor
Department of Pharmacological Sciences, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA
Interests: DDR

Special Issue Information

Dear Colleagues,

It has become increasingly recognized that significant damage to DNA occurs without exposure of cells to exogenous agents (e.g., UV light or chemical mutagens). This endogenous DNA damage arises from the chemical instability of DNA or reactions with intrinsic cellular metabolites, most notably reactive oxygen species, S-adenosylmethionine, and aldehydes. The continuous threat of intracellular genotoxins is held in check by a multiplicity of DNA repair systems that resolve various forms of genomic stress, thereby restoring the genome back to its undamaged state and averting potential mutagenesis, altered transcription products or landscapes, DNA replication fork collapse, and erroneous chromosome transmission. As the same repair pathways act on DNA damage imposed by environmental agents, the level of endogenous damage constitutes a baseline to which exogenous damage is added, such that the effectiveness of defense against external mutagens depends on how well endogenous threats are being handled. Thus, DNA repair pathways comprise a vital array of mechanisms to limit both “spontaneous” mutations and genomic instability by both endogenous and exogenous mechanisms. The same DNA repair pathways are also required for the normal development and function of the immune system. In these ways, DNA repair pathways influence the etiology of cancer, neurodegeneration, autoimmunity, and other diseases, as well as the aging process. Given that genotoxic agents are commonly used in the eradication of cancer cells, DNA repair capacity also influences the effectiveness of cancer treatment. New paradigms are emerging that exploit intrinsic or sporadic DNA repair alterations to enhance therapeutic efficacy. The goal of this Special Issue is to bring together leading scientists to share insights relevant to all the areas above, with the distinction of giving special attention to the endogenous component.

Prof. Dr. David M Wilson III
Prof. Dr. Bruce Demple
Guest Editors

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Published Papers (5 papers)

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Research

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18 pages, 2730 KiB  
Article
REV7 Monomer Is Unable to Participate in Double Strand Break Repair and Translesion Synthesis but Suppresses Mitotic Errors
by Faye M. Vassel, Daniel J. Laverty, Ke Bian, Cortt G. Piett, Michael T. Hemann, Graham C. Walker and Zachary D. Nagel
Int. J. Mol. Sci. 2023, 24(21), 15799; https://doi.org/10.3390/ijms242115799 - 31 Oct 2023
Cited by 1 | Viewed by 1577
Abstract
Rev7 is a regulatory protein with roles in translesion synthesis (TLS), double strand break (DSB) repair, replication fork protection, and cell cycle regulation. Rev7 forms a homodimer in vitro using its HORMA (Hop, Rev7, Mad2) domain; however, the functional importance of Rev7 dimerization [...] Read more.
Rev7 is a regulatory protein with roles in translesion synthesis (TLS), double strand break (DSB) repair, replication fork protection, and cell cycle regulation. Rev7 forms a homodimer in vitro using its HORMA (Hop, Rev7, Mad2) domain; however, the functional importance of Rev7 dimerization has been incompletely understood. We analyzed the functional properties of cells expressing either wild-type mouse Rev7 or Rev7K44A/R124A/A135D, a mutant that cannot dimerize. The expression of wild-type Rev7, but not the mutant, rescued the sensitivity of Rev7−/− cells to X-rays and several alkylating agents and reversed the olaparib resistance phenotype of Rev7−/− cells. Using a novel fluorescent host-cell reactivation assay, we found that Rev7K44A/R124A/A135D is unable to promote gap-filling TLS opposite an abasic site analog. The Rev7 dimerization interface is also required for shieldin function, as both Rev7−/− cells and Rev7−/− cells expressing Rev7K44A/R124A/A135D exhibit decreased proficiency in rejoining some types of double strand breaks, as well as increased homologous recombination. Interestingly, Rev7K44A/R124A/A135D retains some function in cell cycle regulation, as it maintains an interaction with Ras-related nuclear protein (Ran) and partially rescues the formation of micronuclei. The mutant Rev7 also rescues the G2/M accumulation observed in Rev7−/− cells but does not affect progression through mitosis following nocodazole release. We conclude that while Rev7 dimerization is required for its roles in TLS, DSB repair, and regulation of the anaphase promoting complex, dimerization is at least partially dispensable for promoting mitotic spindle assembly through its interaction with Ran. Full article
(This article belongs to the Special Issue Endogenous DNA Damage and Repair)
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11 pages, 2318 KiB  
Article
Maintenance of Flap Endonucleases for Long-Patch Base Excision DNA Repair in Mouse Muscle and Neuronal Cells Differentiated In Vitro
by Rachel A. Caston, Paola Fortini, Kevin Chen, Jack Bauer, Eugenia Dogliotti, Y. Whitney Yin and Bruce Demple
Int. J. Mol. Sci. 2023, 24(16), 12715; https://doi.org/10.3390/ijms241612715 - 12 Aug 2023
Cited by 1 | Viewed by 1254
Abstract
After cellular differentiation, nuclear DNA is no longer replicated, and many of the associated proteins are downregulated accordingly. These include the structure-specific endonucleases Fen1 and DNA2, which are implicated in repairing mitochondrial DNA (mtDNA). Two more such endonucleases, named MGME1 and ExoG, have [...] Read more.
After cellular differentiation, nuclear DNA is no longer replicated, and many of the associated proteins are downregulated accordingly. These include the structure-specific endonucleases Fen1 and DNA2, which are implicated in repairing mitochondrial DNA (mtDNA). Two more such endonucleases, named MGME1 and ExoG, have been discovered in mitochondria. This category of nuclease is required for so-called “long-patch” (multinucleotide) base excision DNA repair (BER), which is necessary to process certain oxidative lesions, prompting the question of how differentiation affects the availability and use of these enzymes in mitochondria. In this study, we demonstrate that Fen1 and DNA2 are indeed strongly downregulated after differentiation of neuronal precursors (Cath.a-differentiated cells) or mouse myotubes, while the expression levels of MGME1 and ExoG showed minimal changes. The total flap excision activity in mitochondrial extracts of these cells was moderately decreased upon differentiation, with MGME1 as the predominant flap endonuclease and ExoG playing a lesser role. Unexpectedly, both differentiated cell types appeared to accumulate less oxidative or alkylation damage in mtDNA than did their proliferating progenitors. Finally, the overall rate of mtDNA repair was not significantly different between proliferating and differentiated cells. Taken together, these results indicate that neuronal cells maintain mtDNA repair upon differentiation, evidently relying on mitochondria-specific enzymes for long-patch BER. Full article
(This article belongs to the Special Issue Endogenous DNA Damage and Repair)
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18 pages, 13461 KiB  
Article
DNA Deamination Is Required for Human APOBEC3A-Driven Hepatocellular Carcinoma In Vivo
by Jordan A. Naumann, Prokopios P. Argyris, Michael A. Carpenter, Harshita B. Gupta, Yanjun Chen, Nuri A. Temiz, Yufan Zhou, Cameron Durfee, Joshua Proehl, Brenda L. Koniar, Silvestro G. Conticello, David A. Largaespada, William L. Brown, Hideki Aihara, Rachel I. Vogel and Reuben S. Harris
Int. J. Mol. Sci. 2023, 24(11), 9305; https://doi.org/10.3390/ijms24119305 - 26 May 2023
Cited by 8 | Viewed by 2350
Abstract
Although the APOBEC3 family of single-stranded DNA cytosine deaminases is well-known for its antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3′s signature single-base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in [...] Read more.
Although the APOBEC3 family of single-stranded DNA cytosine deaminases is well-known for its antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3′s signature single-base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in over 70% of human malignancies and dominate the mutational landscape of numerous individual tumors. Recent murine studies have established cause-and-effect relationships, with both human APOBEC3A and APOBEC3B proving capable of promoting tumor formation in vivo. Here, we investigate the molecular mechanism of APOBEC3A-driven tumor development using the murine Fah liver complementation and regeneration system. First, we show that APOBEC3A alone is capable of driving tumor development (without Tp53 knockdown as utilized in prior studies). Second, we show that the catalytic glutamic acid residue of APOBEC3A (E72) is required for tumor formation. Third, we show that an APOBEC3A separation-of-function mutant with compromised DNA deamination activity and wildtype RNA-editing activity is defective in promoting tumor formation. Collectively, these results demonstrate that APOBEC3A is a “master driver” that fuels tumor formation through a DNA deamination-dependent mechanism. Full article
(This article belongs to the Special Issue Endogenous DNA Damage and Repair)
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Review

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29 pages, 2462 KiB  
Review
The Adaptive Mechanisms and Checkpoint Responses to a Stressed DNA Replication Fork
by Joanne Saldanha, Julie Rageul, Jinal A. Patel and Hyungjin Kim
Int. J. Mol. Sci. 2023, 24(13), 10488; https://doi.org/10.3390/ijms241310488 - 22 Jun 2023
Cited by 4 | Viewed by 3926
Abstract
DNA replication is a tightly controlled process that ensures the faithful duplication of the genome. However, DNA damage arising from both endogenous and exogenous assaults gives rise to DNA replication stress associated with replication fork slowing or stalling. Therefore, protecting the stressed fork [...] Read more.
DNA replication is a tightly controlled process that ensures the faithful duplication of the genome. However, DNA damage arising from both endogenous and exogenous assaults gives rise to DNA replication stress associated with replication fork slowing or stalling. Therefore, protecting the stressed fork while prompting its recovery to complete DNA replication is critical for safeguarding genomic integrity and cell survival. Specifically, the plasticity of the replication fork in engaging distinct DNA damage tolerance mechanisms, including fork reversal, repriming, and translesion DNA synthesis, enables cells to overcome a variety of replication obstacles. Furthermore, stretches of single-stranded DNA generated upon fork stalling trigger the activation of the ATR kinase, which coordinates the cellular responses to replication stress by stabilizing the replication fork, promoting DNA repair, and controlling cell cycle and replication origin firing. Deregulation of the ATR checkpoint and aberrant levels of chronic replication stress is a common characteristic of cancer and a point of vulnerability being exploited in cancer therapy. Here, we discuss the various adaptive responses of a replication fork to replication stress and the roles of ATR signaling that bring fork stabilization mechanisms together. We also review how this knowledge is being harnessed for the development of checkpoint inhibitors to trigger the replication catastrophe of cancer cells. Full article
(This article belongs to the Special Issue Endogenous DNA Damage and Repair)
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19 pages, 4374 KiB  
Review
DNA Glycosylases Define the Outcome of Endogenous Base Modifications
by Lisa Lirussi and Hilde Loge Nilsen
Int. J. Mol. Sci. 2023, 24(12), 10307; https://doi.org/10.3390/ijms241210307 - 18 Jun 2023
Cited by 5 | Viewed by 2370
Abstract
Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell [...] Read more.
Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell fate by regulating chromatin organisation and gene expression. Identical chemical modifications exerting different functions pose a challenge for the cell’s DNA repair machinery, as it needs to accurately distinguish between epigenetic marks and DNA damage to ensure proper repair and maintenance of (epi)genomic integrity. The specificity and selectivity of the recognition of these modified bases relies on DNA glycosylases, which acts as DNA damage, or more correctly, as modified bases sensors for the base excision repair (BER) pathway. Here, we will illustrate this duality by summarizing the role of uracil-DNA glycosylases, with particular attention to SMUG1, in the regulation of the epigenetic landscape as active regulators of gene expression and chromatin remodelling. We will also describe how epigenetic marks, with a special focus on 5-hydroxymethyluracil, can affect the damage susceptibility of nucleic acids and conversely how DNA damage can induce changes in the epigenetic landscape by altering the pattern of DNA methylation and chromatin structure. Full article
(This article belongs to the Special Issue Endogenous DNA Damage and Repair)
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