title: FANCJ localization by mismatch repair is vital to maintain genomic integrity after UV irradiation.
abstract: 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.
authors.affiliation: Authors' Affiliations: Department of Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, Massachusetts; and Department of Pharmacological Sciences & Department of Chemistry, Stony Brook University, Stony Brook, New York.
authors.forename: Shawna
authors.initials: S
authors.lastname: Guillemette
authors.forename: Amy
authors.initials: A
authors.lastname: Branagan
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.forename: Aashana
authors.initials: A
authors.lastname: Dhruva
authors.forename: Orlando D
authors.initials: OD
authors.lastname: Schärer
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Cantor
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects; D053843:DNA Mismatch Repair; D004260:DNA Repair; D004261:DNA Replication / Q000528:radiation effects; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability / Q000528:radiation effects*; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000528:radiation effects; D010766:Phosphorylation; D021381:Protein Transport; D051716:Replication Protein A / Q000378:metabolism; D016196:S Phase / Q000235:genetics / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D051716:Replication Protein A