ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair

作者：Chen Chun Chin; Kass Elizabeth M; Yen Wei Feng; Ludwig Thomas; Moynahan Mary Ellen; Chaudhuri Jayanta; Jasin Maria

来源：Proceedings of the National Academy of Sciences, 2017, 114(29): 7665-7670.

DOI：10.1073/pnas.1706392114

• ATM
• BRCA1
• homology-directed repair
• homologous recombination
• olaparib

BRCA1 is essential for homology-directed repair (HDR) of DNA double-strand breaks in part through antagonism of the nonhomologous end-joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling and repair, but how ATM participates in HDR and genetically interacts with BRCA1 in this process is unclear. To investigate this question, we used the Brca1(S1598F) mouse model carrying a mutation in the BRCA1 C-terminal domain of BRCA1. Whereas ATM loss leads to a mild HDR defect in adult somatic cells, we find that ATM inhibition leads to severely reduced HDR in Brca1(S1598F) cells. Consistent with a critical role for ATM in HDR in this background, loss of ATM leads to synthetic lethality of Brca1(S1598F) mice. Whereas both ATM and BRCA1 promote end resection, which can be regulated by 53BP1, 53bp1 deletion does not rescue the HDR defects of Atm mutant cells, in contrast to Brca1 mutant cells. These results demonstrate that ATM has a role in HDR independent of the BRCA1-53BP1 antagonism and that its HDR function can become critical in certain contexts.

• 出版日期2017-7-18