DNA mismatch repair mediates protection from mutagenesis induced by short-wave ultraviolet light

Borgdorff, Viola; Pauw, Bea; Hees-Stuivenberg, Sandrine van; Wind, Niels de

doi:10.1016/j.dnarep.2006.06.005

Cited by 20 publications

(25 citation statements)

References 39 publications

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“…Given that FANCJ is dispensable for survival after UV exposure (28), we sought to examine if FANCJ preserves the integrity of the genome, as has been found for MMR (14). A549 cells are useful for analyzing mutations at the endogenous HPRT locus (36).…”

Section: Resultsmentioning

confidence: 99%

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FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation

et al. 2014

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Nucleotide excision repair (NER) is critical for the repair of DNA lesions induced by UV radiation, but its contribution in replicating cells is less clear. Here, we show that dual incision by NER endonucleases, including XPF and XPG, promotes the S-phase accumulation of the BRCA1 and Fanconi anemia–associated DNA helicase FANCJ to sites of UV-induced damage. FANCJ promotes replication protein A phosphorylation and the arrest of DNA synthesis following UV irradiation. Interaction defective mutants of FANCJ reveal that BRCA1 binding is not required for FANCJ localization, whereas interaction with the mismatch repair (MMR) protein MLH1 is essential. Correspondingly, we find that FANCJ, its direct interaction with MLH1, and the MMR protein MSH2 function in a common pathway in response to UV irradiation. FANCJ-deficient cells are not sensitive to killing by UV irradiation, yet we find that DNA mutations are significantly enhanced. Thus, we considered that FANCJ deficiency could be associated with skin cancer. Along these lines, in melanoma we found several somatic mutations in FANCJ, some of which were previously identified in hereditary breast cancer and Fanconi anemia. Given that, mutations in XPF can also lead to Fanconi anemia, we propose collaborations between Fanconi anemia, NER, and MMR are necessary to initiate checkpoint activation in replicating human cells to limit genomic instability.

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Section: Resultsmentioning

confidence: 99%

“…MMR factors induce checkpoints, apoptosis, preserve genomic stability, and suppress cancer induced by UV irradiation (10-14). The mechanism by which MMR functions in response to UV irradiation could stem from its general role in genome surveillance and mismatch correction.…”

Section: Introductionmentioning

confidence: 99%

FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation

et al. 2014

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“…Another mechanism to potentially increase the in vivo fidelity of TLS is correction by DNA mismatch repair, as has been previously suggested (57). There is ample evidence that the main mismatch recognition complex hMutSα can bind to mismatched photoproduct lesions (57)(58)(59), and a recent report suggests that mismatch repair does indeed aid in controlling mutagenesis induced by UV light (60). These error correction processes seem feasible because, unlike certain other types of lesions, the template bases in CPDs retain Watson-Crick and Hoogsteen base pairing potential (61,62).…”

Section: Discussionmentioning

confidence: 97%

Effects of Accessory Proteins on the Bypass of a cis-syn Thymine−Thymine Dimer by Saccharomyces cerevisiae DNA Polymerase η

et al. 2007

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Among several hypotheses to explain how translesion synthesis (TLS) by DNA polymerase η (pol η) suppresses ultraviolet light-induced mutagenesis in vivo despite the fact that pol η copies DNA with low fidelity, here we test whether replication accessory proteins enhance the fidelity of TLS by pol η. We first show that the single-stranded DNA binding protein RPA, the sliding clamp PCNA, and the clamp loader RFC slightly increase the processivity of yeast pol η and its ability to recycle to new template primers. However, these increases are small, and they are similar when copying an undamaged template and a template containing a cis-syn TT dimer. Consequently, the accessory proteins do not strongly stimulate the already robust TT dimer bypass efficiency of pol η. We then perform a comprehensive analysis of yeast pol η fidelity. We show that it is much less accurate than other yeast DNA polymerases and that the accessory proteins have little effect on fidelity when copying undamaged templates or when bypassing a TT dimer. Thus, although accessory proteins clearly participate in pol η functions in vivo, they do not appear to help suppress UV mutagenesis by improving pol η bypass fidelity per se.Translesion synthesis (TLS 1 ) is one mechanism of damage tolerance employed by cells when synthesis by the major replicative polymerases is blocked by lesions. Several polymerases in different families have been shown to bypass lesions in vitro (see ref 1 and references therein). Of these, the role of pol η in the bypass of UV photoproducts is the best understood. In humans, the loss of pol η causes the variant (XP-V) form of xeroderma pigmentosum (2,3), a disease characterized by greatly increased susceptibility to sunlight-induced skin cancer (see refs 4 and 5 and references therein). A key property of human and yeast cells lacking pol η is increased mutagenesis following exposure to ultraviolet light (6-13). A key property of human and yeast pol η is its ability to bypass cyclobutane pyrimidine dimers (CPDs) with much higher efficiency than that of other eukaryotic DNA polymerases (14-18). These facts imply that pol η participates in the bypass of slowly repaired cyclobutane pyrimidine dimers in a manner that avoids mutations such that in its absence, other polymerases perform mutagenic bypass that ultimately results in skin cancer. Consistent with the participation of pol η in CPD bypass that avoids mutations are seminal studies of single nucleotide insertion (17,19,20), demonstrating that yeast and human pol η preferentially insert dAMP opposite both template thymines of a cis-syn thymine-thymine dimer (TTD). This selectivity for inserting a correct nucleotide undoubtedly contributes to CPD bypass in cells that reduces UV-induced mutagenesis in humans, mice, and yeast. The actual rate of base substitutions generated per CPD bypass event in human cells is unknown. Fortunately, quantitative in vivo measurements in S. cerevisiae are available and indicate that bypass of TC and CC dimers generates less than one bas...

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“…Similarly, hMSH2 is implicated in cell cycle arrest and apoptosis in melanocytes [121]. MMR-deficient mammalian cell lines or murine embryonic stem cells exhibit increased mutagenesis upon UV exposure compared to MMR-proficient cells [122,123]. MutSα can bind to mismatched but not matched CPD and (6-4)PP in vitro [124,125].…”

Section: Oxidative Damage and Dna Adductsmentioning

confidence: 99%

DNA mismatch repair and the DNA damage response

2016

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This review discusses the role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the focus is on findings from mammalian cells, much has been learned from studies in other organisms including bacteria and yeast [1,2]. MMR promotes a DDR mediated by a key signaling kinase, ATM and Rad3-related (ATR), in response to various types of DNA damage including some encountered in widely used chemotherapy regimes. An introduction to the DDR mediated by ATR reveals its immense complexity and highlights the many biological and mechanistic questions that remain. Recent findings and future directions are highlighted.

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DNA mismatch repair mediates protection from mutagenesis induced by short-wave ultraviolet light

Cited by 20 publications

References 39 publications

FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation

FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation

Effects of Accessory Proteins on the Bypass of a cis-syn Thymine−Thymine Dimer by Saccharomyces cerevisiae DNA Polymerase η

DNA mismatch repair and the DNA damage response

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