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RAD51B-RAD51C-RAD51D-XRCC2 肿瘤抑制因子的结构与功能。

Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tumour suppressor.

机构信息

The Francis Crick Institute, London, UK.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

出版信息

Nature. 2023 Jul;619(7970):650-657. doi: 10.1038/s41586-023-06179-1. Epub 2023 Jun 21.

DOI:10.1038/s41586-023-06179-1
PMID:37344587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7614784/
Abstract

Homologous recombination is a fundamental process of life. It is required for the protection and restart of broken replication forks, the repair of chromosome breaks and the exchange of genetic material during meiosis. Individuals with mutations in key recombination genes, such as BRCA2 (also known as FANCD1), or the RAD51 paralogues RAD51B, RAD51C (also known as FANCO), RAD51D, XRCC2 (also known as FANCU) and XRCC3, are predisposed to breast, ovarian and prostate cancers and the cancer-prone syndrome Fanconi anaemia. The BRCA2 tumour suppressor protein-the product of BRCA2-is well characterized, but the cellular functions of the RAD51 paralogues remain unclear. Genetic knockouts display growth defects, reduced RAD51 focus formation, spontaneous chromosome abnormalities, sensitivity to PARP inhibitors and replication fork defects, but the precise molecular roles of RAD51 paralogues in fork stability, DNA repair and cancer avoidance remain unknown. Here we used cryo-electron microscopy, AlphaFold2 modelling and structural proteomics to determine the structure of the RAD51B-RAD51C-RAD51D-XRCC2 complex (BCDX2), revealing that RAD51C-RAD51D-XRCC2 mimics three RAD51 protomers aligned within a nucleoprotein filament, whereas RAD51B is highly dynamic. Biochemical and single-molecule analyses showed that BCDX2 stimulates the nucleation and extension of RAD51 filaments-which are essential for recombinational DNA repair-in reactions that depend on the coupled ATPase activities of RAD51B and RAD51C. Our studies demonstrate that BCDX2 orchestrates RAD51 assembly on single stranded DNA for replication fork protection and double strand break repair, in reactions that are critical for tumour avoidance.

摘要

同源重组是生命的基本过程。它是保护和重启断裂复制叉、修复染色体断裂以及在减数分裂过程中交换遗传物质所必需的。关键重组基因（如 BRCA2（也称为 FANCD1）或 RAD51 同源物 RAD51B、RAD51C（也称为 FANCO）、RAD51D、XRCC2（也称为 FANCU）和 XRCC3）发生突变的个体易患乳腺癌、卵巢癌和前列腺癌以及癌症易感综合征范可尼贫血症。BRCA2 肿瘤抑制蛋白（BRCA2 的产物）的特性得到了很好的描述，但 RAD51 同源物的细胞功能仍不清楚。遗传敲除显示生长缺陷、RAD51 焦点形成减少、自发染色体异常、对 PARP 抑制剂和复制叉缺陷的敏感性，但 RAD51 同源物在叉稳定性、DNA 修复和癌症预防中的精确分子作用仍不清楚。在这里，我们使用低温电子显微镜、AlphaFold2 建模和结构蛋白质组学来确定 RAD51B-RAD51C-RAD51D-XRCC2 复合物（BCDX2）的结构，揭示 RAD51C-RAD51D-XRCC2 模拟了三个 RAD51 原聚体在核蛋白丝内排列，而 RAD51B 则高度动态。生化和单分子分析表明，BCDX2 刺激 RAD51 丝的成核和延伸，这对于重组 DNA 修复至关重要，反应依赖于 RAD51B 和 RAD51C 的偶联 ATP 酶活性。我们的研究表明，BCDX2 协调 RAD51 在单链 DNA 上的组装，以保护复制叉并修复双链断裂，这对于肿瘤预防至关重要。

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