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

Significance The tumor suppressors BRCA1 and ATM have both been implicated in the early steps of homologous recombination, also termed homology-directed repair (HDR). However, how ATM genetically interacts with BRCA1 in this process is unclear. In mice carrying a breast cancer-derived mutation in the BRCA1 C-terminal (BRCT) domain, we find that ATM becomes essential for supporting the residual levels of HDR necessary to repair a DNA break. ATM-mediated HDR is not affected by the status of 53BP1, an antagonizing factor of BRCA1. ATM loss is associated with synthetic lethality of BRCT mutant mice, which provides insight into the therapeutic potential of utilizing ATM kinase inhibitors in combination with PARP-inhibitor therapy for certain BRCA1-deficient tumors. 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 Brca1S1598F 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 Brca1S1598F cells. Consistent with a critical role for ATM in HDR in this background, loss of ATM leads to synthetic lethality of Brca1S1598F 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.

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