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BRCA2 基因 DNA 结合和 C 末端结构域在其 DNA 修复过程中的移动性和构象中的作用。

Role of BRCA2 DNA-binding and C-terminal domain in its mobility and conformation in DNA repair.

机构信息

Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.

Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, Netherlands.

出版信息

Elife. 2021 Jul 13;10:e67926. doi: 10.7554/eLife.67926.

DOI:10.7554/eLife.67926
PMID:34254584
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8324294/
Abstract

Breast cancer type two susceptibility protein (BRCA2) is an essential protein in genome maintenance, homologous recombination (HR), and replication fork protection. Its function includes multiple interaction partners and requires timely localization to relevant sites in the nucleus. We investigated the importance of the highly conserved DNA-binding domain (DBD) and C-terminal domain (CTD) of BRCA2. We generated BRCA2 variants missing one or both domains in mouse embryonic stem (ES) cells and defined their contribution in HR function and dynamic localization in the nucleus, by single-particle tracking of BRCA2 mobility. Changes in molecular architecture of BRCA2 induced by binding partners of purified BRCA2 were determined by scanning force microscopy. BRCA2 mobility and DNA-damage-induced increase in the immobile fraction were largely unaffected by C-terminal deletions. The purified proteins missing CTD and/or DBD were defective in architectural changes correlating with reduced HR function in cells. These results emphasize BRCA2 activity at sites of damage beyond promoting RAD51 delivery.

摘要

乳腺癌类型 2 易感性蛋白（BRCA2）是基因组维护、同源重组（HR）和复制叉保护的必需蛋白。它的功能包括多个相互作用伙伴，并且需要及时定位于细胞核中的相关部位。我们研究了 BRCA2 的高度保守 DNA 结合域（DBD）和 C 末端结构域（CTD）的重要性。我们在小鼠胚胎干细胞（ES 细胞）中生成缺失一个或两个结构域的 BRCA2 变体，并通过单颗粒跟踪 BRCA2 的流动性来定义它们在 HR 功能和核内动态定位中的贡献。通过扫描力显微镜确定由纯化 BRCA2 的结合伙伴诱导的 BRCA2 分子结构变化。由结合伴侣结合引起的 BRCA2 移动性和 DNA 损伤诱导的无移动部分的增加在很大程度上不受 C 末端缺失的影响。缺失 CTD 和/或 DBD 的纯化蛋白在与细胞中 HR 功能降低相关的结构变化方面存在缺陷。这些结果强调了 BRCA2 在损伤部位的活性，而不仅仅是促进 RAD51 的传递。

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