XPF and XPG promotes the S-phase accumulation of the BRCA1 and Fanconi anemia (FA)-associated DNA helicase FANCJ to sites of UV-induced damage. In response to UV damage, FANCJ promotes RPA phosphorylation and the arrest of DNA synthesis following UV

The authors disclose no potential conflicts of interest. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Nucleotide excision repair (NER) is critical for the repair of DNA lesions induced by ultraviolet (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 (FA)-associated DNA helicase FANCJ to sites of UV-induced damage. In response to UV damage, FANCJ promotes RPA 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 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 (FA). Given that mutations in XPF can also lead to FA, we propose collaborations between FA, NER and MMR are necessary to initiate checkpoint activation in replicating human cells to limit genomic instability. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.