REV7 counteracts DNA double-strand break resection and affects PARP inhibition.
REV7 counteracts DNA double-strand break resection and affects PARP inhibition.
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DOI：
10.1038/nature14328
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发表时间：
2015-05-28
期刊：
影响因子：
64.8
通讯作者：
Rottenberg S
中科院分区：
文献类型：
--
作者：
Xu G;Chapman JR;Brandsma I;Yuan J;Mistrik M;Bouwman P;Bartkova J;Gogola E;Warmerdam D;Barazas M;Jaspers JE;Watanabe K;Pieterse M;Kersbergen A;Sol W;Celie PHN;Schouten PC;van den Broek B;Salman A;Nieuwland M;de Rink I;de Ronde J;Jalink K;Boulton SJ;Chen J;van Gent DC;Bartek J;Jonkers J;Borst P;Rottenberg S
DNA双链断裂(DSB)的无错修复是通过同源重组(HR)实现的，而BRCA1是这一修复途径的重要因子。在没有BRCA1介导的HR的情况下，给药PARP抑制剂可以诱导乳腺癌或卵巢癌患者的肿瘤细胞合成杀伤力。尽管这种量身定做的治疗方法有好处，但HR恢复可能会产生耐药性。BRCA1失活突变的遗传逆转可能是耐药的潜在机制，但这并不能解释所有情况下的耐药性。特别是，对BRCA1非依赖性HR的恢复知之甚少。在这里，我们证明了Rev7(也称为MAD2L2)的丢失在BRCA1缺陷细胞中重新建立了依赖CtIP的DSB的末端切除，导致HR恢复和PARP抑制剂耐药性，并被ATM激酶抑制逆转。Rev7以一种依赖于H2 AX-MDC1-RNF8-RNF168-53BP1染色质途径的方式被招募到DSB，除了在DNA损伤耐受中的调节作用外，它似乎还阻止HR和促进末端连接。最后，我们建立了Rev7阻断DSB切除以促进免疫球蛋白类开关重组过程中的非同源末端连接(NHEJ)。我们的结果揭示了53BP1下游Rev7在协调BRCA1缺陷细胞中病理性DSB修复途径选择方面意想不到的关键功能。
Error-free repair of DNA double-strand breaks (DSB) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, administration of PARP inhibitors induces synthetic lethality of tumor cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here, we show that loss of REV7 (also known as MAD2L2) re-establishes CtIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and appears to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining (NHEJ) during immunoglobulin class switch recombination. Our results reveal an unexpected critical function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.