A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination.
A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination.
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DOI：
10.1038/s41467-021-26079-0
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发表时间：
2021-09-30
影响因子：
16.6
通讯作者：
Nilsson J
中科院分区：
文献类型：
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作者：
Ambjørn SM;Duxin JP;Hertz EPT;Nasa I;Duro J;Kruse T;Lopez-Mendez B;Rymarczyk B;Cressey LE;van Overeem Hansen T;Kettenbach AN;Oestergaard VH;Lisby M;Nilsson J
肿瘤抑制基因BRCA 2的突变与乳腺癌和卵巢癌的易感性有关。BRCA 2通过同源重组（HR）促进毒性DNA双链断裂（DSB）的修复，在维持基因组完整性方面发挥核心作用。BRCA 2通过控制切除的单链DNA上的RAD 51核蛋白丝的形成来起作用，但是在HR期间BRCA 2活性如何被调节还不完全清楚。在这里，我们描绘了一个途径，ATM和ATR激酶磷酸化BRCA 2的高度保守的区域，在响应DSBs。这些磷酸化通过保守的结合基序刺激蛋白磷酸酶PP 2A-B56与BRCA 2的结合。我们表明，磷酸化依赖的BRCA 2-PP 2A-B56复合物的形成是需要有效的RAD 51丝形成在DNA损伤和HR介导的DNA修复的网站。此外，我们发现BRCA 2中的几种癌症相关突变使BRCA 2-PP 2A-B56相互作用失调，并使细胞对PARP抑制敏感。总的来说，我们的工作揭示了PP 2A-B56作为HR中BRCA 2功能的正调节因子，对BRCA 2和PP 2A-B56突变的癌症具有临床意义。BRCA 2在通过同源重组（HR）促进DNA修复中起核心作用。在这里，作者描述了BRCA 2如何与蛋白磷酸酶PP 2A-B56形成复合物，以响应HR所需的DNA损伤。
Mutations in the tumour suppressor gene BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by controlling RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 filament formation at sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers. BRCA2 plays a central role in facilitating DNA repair by homologous recombination (HR). Here the authors describe how BRCA2 forms a complex with the protein phosphatase PP2A-B56 in response to DNA damage, which is required for HR.