ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair
ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair
复制标题
DOI：
10.1073/pnas.1706392114
复制
发表时间：
2017-07-18
影响因子：
11.1
通讯作者：
Jasin, Maria
中科院分区：
文献类型：
--
作者：
Chen, Chun-Chin;Kass, Elizabeth M.;Jasin, Maria
BRCA1对DNA双链断裂的同源定向修复（HDR）至关重要，部分通过拮抗非同源末端连接因子53BP1。ATM激酶参与DNA损伤信号传导和修复的各个方面，但ATM如何参与HDR并在此过程中与BRCA1基因相互作用尚不清楚。为了研究这个问题，我们使用了携带Brca1 c端结构域突变的Brca1（S1598F）小鼠模型。尽管ATM缺失导致成人体细胞轻度HDR缺陷，但我们发现ATM抑制导致Brca1（S1598F）细胞中HDR严重降低。在这种背景下，与ATM在HDR中的关键作用一致，ATM的缺失导致Brca1（S1598F）小鼠的合成致死。虽然ATM和BRCA1都促进末端切除，而末端切除可由53BP1调节，但与BRCA1突变细胞相比，53BP1的缺失并不能挽救ATM突变细胞的HDR缺陷。这些结果表明，ATM在HDR中具有独立于BRCA1-53BP1拮抗的作用，并且其HDR功能在某些情况下可能变得至关重要。
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.