Mismatch repair protein MSH2 regulates translesion DNA synthesis following exposure of cells to UV radiation

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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“…S9A–S9C). Correspondingly, MSH2-deficient cells have defective UV-induced PCNA mono-ubiquitination and TLS foci formation (58). …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…The relationship between DNA damage and DNA repair is complex; no single pathway efficiently repairs all types of DNA lesions, some lesions are substrates for more than one pathway, and evidence for extensive interactions among proteins involved in distinct pathways continues to emerge (6-11). Mutations in DNA repair genes can have profound consequences for disease risk.…”

Section: Introductionmentioning

confidence: 99%

Inter-individual variation in DNA repair capacity: A need for multi-pathway functional assays to promote translational DNA repair research

2014

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Why does a constant barrage of DNA damage lead to disease in some individuals, while others remain healthy? This article surveys current work addressing the implications of inter-individual variation in DNA repair capacity for human health, and discusses the status of DNA repair assays as potential clinical tools for personalized prevention or treatment of disease. In particular, we highlight research showing that there are significant inter-individual variations in DNA Repair Capacity (DRC), and that measuring these differences provides important biological insight regarding disease susceptibility and cancer treatment efficacy. We emphasize work showing that it is important to measure repair capacity in multiple pathways, and that functional assays are required to fill a gap left by genome wide association studies, global gene expression and proteomics. Finally, we discuss research that will be needed to overcome barriers that currently limit the use of DNA repair assays in the clinic.

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“…MSH2-MSH3 plays roles as a co-factor in BER [94,98,99], transcription-coupled repair (TCR) [136–138] and double strand break repair (DSBR) [137,139,140]. Each of these pathways has been implicated in CAG instability in mice [58,77–79, 81–83, 94], and classically operates with distinct Family A, B, X or Y polymerases, depending on the pathway (Table 2).…”

Section: Encountering Bumps Within Triplet Repeat Tractsmentioning

confidence: 99%

Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts

Polyzos

McMurray

2017

DNA Repair

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Expansion of simple triplet repeats (TNR) underlies more than 30 severe degenerative diseases. There is a good understanding of the major pathways generating an expansion, and the associated polymerases that operate during gap filling synthesis at these “difficult to copy” sequences. However, the mechanism by which a TNR is repaired depends on the type of lesion, the structural features imposed by the lesion, the assembled replication/ repair complex, and the polymerase that encounters it. The relationships among these parameters are exceptionally complex and how they direct pathway choice is poorly understood. In this review, we consider the properties of polymerases, and how encounters with GC-rich or abnormal structures might influence polymerase choice and the success of replication and repair. Insights over the last three years have highlighted new mechanisms that provide interesting choices to consider in protecting genome stability.

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Mismatch repair protein MSH2 regulates translesion DNA synthesis following exposure of cells to UV radiation

Cited by 29 publications

References 49 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

Inter-individual variation in DNA repair capacity: A need for multi-pathway functional assays to promote translational DNA repair research

Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts

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