MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells.,Nature Communications

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MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells.
Nature Communications ( IF 14.7 ) Pub Date : 2017-10-16 , DOI: 10.1038/s41467-017-01180-5
Delphine Lemaçon ₁ , Jessica Jackson ₁ , Annabel Quinet ₁ , Joshua R Brickner ₂ , Shan Li ₃ , Stephanie Yazinski ₄ , Zhongsheng You ₃ , Grzegorz Ira ₅ , Lee Zou ₄ , Nima Mosammaparast ₂ , Alessandro Vindigni ₁

Affiliation

The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MRE11 nuclease, leading to chemotherapeutic sensitivity. Here we report that BRCA proteins prevent nucleolytic degradation by protecting replication forks that have undergone fork reversal upon drug treatment. The unprotected regressed arms of reversed forks are the entry point for MRE11 in BRCA-deficient cells. The CtIP protein initiates MRE11-dependent degradation, which is extended by the EXO1 nuclease. Next, we show that the initial limited resection of the regressed arms establishes the substrate for MUS81 in BRCA2-deficient cells. In turn, MUS81 cleavage of regressed forks with a ssDNA tail promotes POLD3-dependent fork rescue. We propose that targeting this pathway may represent a new strategy to modulate BRCA2-deficient cancer cell response to chemotherapeutics that cause fork degradation.BRCA proteins have emerged as key stabilizing factors for the maintenance of replication forks following replication stress. Here the authors describe how reversed replication forks are degraded in the absence of BRCA2, and a MUS81 and POLD3-dependent mechanism of rescue following the withdrawal of genotoxic agent.

中文翻译：

MRE11和EXO1核酸酶降解反向叉，并在BRCA2缺陷型细胞中引起MUS81依赖性叉拯救。

乳腺癌易感性蛋白BRCA1和BRCA2已成为复制压力后维持复制叉完整性的关键稳定因素。在缺少它们的情况下，停滞的复制叉会被MRE11核酸酶广泛降解，从而导致化疗敏感性。在这里，我们报告说，BRCA蛋白通过保护在药物治疗后发生叉子逆转的复制叉子来防止核酸降解。反向叉的无保护的反向臂是BRCA缺陷细胞中MRE11的切入点。CtIP蛋白启动了MRE11依赖性降解，该降解通过EXO1核酸酶延长。接下来，我们显示了回归臂的初始有限切除在BRCA2缺陷细胞中建立了MUS81的底物。反过来，MUS81切割带有ssDNA尾巴的前叉促进了POLD3依赖性前叉的抢救。我们建议靶向该途径可能代表一种调节BRCA2缺陷型癌细胞对导致叉子降解的化学治疗药物反应的新策略.BRCA蛋白已成为复制应激后维持复制叉子的关键稳定因素。在这里，作者描述了在不存在BRCA2的情况下反向复制叉如何降解，以及遗传毒性剂退出后MUS81和POLD3依赖性的抢救机制。在复制压力后，BRCA蛋白已成为维持复制叉的关键稳定因子。在这里，作者描述了在不存在BRCA2的情况下反向复制叉如何降解，以及遗传毒性剂退出后MUS81和POLD3依赖性的抢救机制。在复制压力后，BRCA蛋白已成为维持复制叉的关键稳定因子。在这里，作者描述了在不存在BRCA2的情况下反向复制叉如何降解，以及遗传毒性剂退出后MUS81和POLD3依赖性的抢救机制。

更新日期：2017-10-16

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