A phosphorylation-deubiquitination cascade regulates the BRCA2-RAD51 axis in homologous recombination.
A phosphorylation-deubiquitination cascade regulates the BRCA2-RAD51 axis in homologous recombination.
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DOI：
10.1101/gad.289439.116
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发表时间：
2016-12-01
影响因子：
10.5
通讯作者：
Lou Z
中科院分区：
文献类型：
--
作者：
Luo K;Li L;Li Y;Wu C;Yin Y;Chen Y;Deng M;Nowsheen S;Yuan J;Lou Z
在本研究中，Luo等人研究了DNA双链断裂（DSB）修复过程中BRCA2-RAD51轴在同源重组（HR）中的调控。作者确定UCHL3是DNA修复的一种新的调节因子，并提出了一个磷酸化-去泛素化级联动态调节BRCA2-RAD51通路的模型。同源重组（Homologous recombination， HR）是哺乳动物细胞DNA双链断裂（DSB）修复的主要途径之一。HR缺陷引发基因组不稳定并导致癌症易感性。HR的定义步骤是由RAD51蛋白引导的同源链交换，RAD51蛋白被BRCA2招募到dsb中。然而，BRCA2-RAD51轴的调控尚不清楚。在这里，我们报道RAD51的泛素化阻碍了RAD51 - brca2的相互作用，而RAD51的去泛素化促进了RAD51 - brca2的结合和RAD51的招募，因此对适当的HR至关重要。机制上，在对DNA损伤的反应中，去泛素酶UCHL3被ATM磷酸化并激活。UCHL3反过来使RAD51去泛素化并促进RAD51与BRCA2之间的结合。UCHL3的过表达使乳腺癌细胞对放疗和化疗产生耐药性，而UCHL3的缺失使细胞对这些治疗变得敏感，这表明UCHL3在癌症治疗中起决定性作用。总之，我们确定UCHL3是DNA修复的一种新的调节因子，并揭示了一个磷酸化-去泛素化级联动态调节BRCA2-RAD51通路的模型。
In this study, Luo et al. investigated the regulation of the BRCA2–RAD51 axis in homologous recombination (HR) during DNA double-strand break (DSB) repair. The authors identify UCHL3 as a novel regulator of DNA repair and propose a model in which a phosphorylation–deubiquitination cascade dynamically regulates the BRCA2–RAD51 pathway. Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2–RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51–BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51–BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation–deubiquitination cascade dynamically regulates the BRCA2–RAD51 pathway.
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影响因子：
16.8
作者：
Conway, AB;Lynch, TW;Rice, PA
通讯作者：
Rice, PA
DOI：
10.1016/j.cub.2009.05.057
发表时间：
2009-07-14
期刊：
Current biology : CB
影响因子：
--
作者：
Ayoub N;Rajendra E;Su X;Jeyasekharan AD;Mahen R;Venkitaraman AR
通讯作者：
Venkitaraman AR
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
64.8
作者：
Esashi, F;Christ, N;West, SC
通讯作者：
West, SC
影响因子：
10.5
作者：
Galanty, Yaron;Belotserkovskaya, Rimma;Jackson, Stephen P.
通讯作者：
Jackson, Stephen P.