Targeting the FANCJ-BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass.
BRCA1 and the DNA helicase FANCJ (also known as BACH1 or BRIP1) have common functions in breast cancer suppression and DNA repair. However, the functional significance of the direct interaction between BRCA1 and FANCJ remains unclear. Here, we have discovered that BRCA1 binding to FANCJ regulates DNA damage repair choice. Thus, when FANCJ binding to BRCA1 is ablated, the molecular mechanism chosen for the repair of damaged DNA is dramatically altered. Specifically, a FANCJ protein that cannot be phosphorylated at serine 990 or bind BRCA1 inhibits DNA repair via homologous recombination and promotes poleta-dependent bypass. Furthermore, the poleta-dependent bypass promoted by FANCJ requires the direct binding to the mismatch repair (MMR) protein, MLH1. Together, our findings implicate that in human cells BRCA1 binding to FANCJ is critical to regulate DNA repair choice and promote genomic stability. Moreover, unregulated FANCJ function could be associated with cancer and/or chemoresistance.
Xie
J
J
Department of Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA 01605, USA.
Litman
R
R
Wang
S
S
Peng
M
M
Guillemette
S
S
Rooney
T
T
Cantor
S B
SB
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D019313:BRCA1 Protein / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D051856:Fanconi Anemia Complementation Group Proteins / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D000099270:Y-Family DNA Polymerases
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D050976:Basic-Leucine Zipper Transcription Factors; D004259:DNA-Directed DNA Polymerase; D051856:Fanconi Anemia Complementation Group Proteins; D016685:Mitomycin; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins; C102108:BACH1 protein, human; C492913:BRCA1 protein, human; C501486:MLH1 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases