title: The Fanconi anemia core complex is required for efficient point mutagenesis and Rev1 foci assembly.
abstract: Fanconi anemia (FA) is a chromosome instability syndrome characterized by congenital abnormalities, cellular hypersensitivity to DNA crosslinking agents, and heightened cancer risk. Eight of the thirteen identified FA genes encode subunits of a nuclear FA core complex that monoubiquitinates FANCD2 and FANCI to maintain genomic stability in response to replication stress. The FA pathway has been implicated in the regulation of error-prone DNA damage tolerance via an undefined molecular mechanism. Here, we show that the FA core complex is required for efficient spontaneous and UVC-induced point mutagenesis, independently of FANCD2 and FANCI. Consistent with the observed hypomutability of cells deficient in the FA core complex, we also demonstrate that these cells are impaired in the assembly of the error-prone translesion DNA synthesis polymerase Rev1 into nuclear foci. Consistent with a role downstream of the FA core complex and like known FA proteins, Rev1 is required to prevent DNA crosslinker-induced chromosomal aberrations in human cells. Interestingly, proliferating cell nuclear antigen (PCNA) monoubiquitination, known to contribute to Rev1 recruitment, does not require FA core complex function. Our results suggest a role for the FA core complex in regulating Rev1-dependent DNA damage tolerance independently of FANCD2, FANCI, and PCNA monoubiquitination.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kanchan D
authors.initials: KD
authors.lastname: Mirchandani
authors.forename: Ryan M
authors.initials: RM
authors.lastname: McCaffrey
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002869:Chromosome Aberrations; D004249:DNA Damage; D017931:DNA Primers; D005199:Fanconi Anemia / Q000235:genetics*; D006801:Humans; D008856:Microscopy, Fluorescence; D016685:Mitomycin / Q000494:pharmacology; D016296:Mutagenesis
chemical_list: D017931:DNA Primers; D016685:Mitomycin