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RAD51功能分离突变会使复制叉维持功能失效，但能保留双链断裂修复功能。

RAD51 separation of function mutation disables replication fork maintenance but preserves DSB repair.

作者信息

Son Mi Young, Belan Ondrej, Spirek Mario, Cibulka Jakub, Nikulenkov Fedor, Kim You Young, Hwang Sunyoung, Myung Kyungjae, Montagna Cristina, Kim Tae Moon, Krejci Lumir, Hasty Paul

机构信息

Department of Molecular Medicine, The Barshop Institute for Longevity and Aging Studies, The Cancer Therapy Research Center, UT Health San Antonio, San Antonio, TX 78229, USA.

Department of Biology, Masaryk University, 625 00 Brno, Czech Republic.

出版信息

iScience. 2024 Mar 16;27(4):109524. doi: 10.1016/j.isci.2024.109524. eCollection 2024 Apr 19.

DOI:10.1016/j.isci.2024.109524
PMID:38577109
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10993188/
Abstract

Homologous recombination (HR) protects replication forks (RFs) and repairs DNA double-strand breaks (DSBs). Within HR, BRCA2 regulates RAD51 via two interaction regions: the BRC repeats to form filaments on single-stranded DNA and exon 27 (Ex27) to stabilize the filament. Here, we identified a RAD51 S181P mutant that selectively disrupted the RAD51-Ex27 association while maintaining interaction with BRC repeat and proficiently forming filaments capable of DNA binding and strand invasion. Interestingly, RAD51 S181P was defective for RF protection/restart but proficient for DSB repair. Our data suggest that Ex27-mediated stabilization of RAD51 filaments is required for the protection of RFs, while it seems dispensable for the repair of DSBs.

摘要

同源重组（HR）可保护复制叉（RFs）并修复DNA双链断裂（DSBs）。在HR过程中，BRCA2通过两个相互作用区域调节RAD51：BRC重复序列以在单链DNA上形成细丝，以及外显子27（Ex27）以稳定细丝。在此，我们鉴定出一种RAD51 S181P突变体，该突变体选择性破坏RAD51与Ex27的结合，同时保持与BRC重复序列的相互作用，并能高效形成能够进行DNA结合和链侵入的细丝。有趣的是，RAD51 S181P在RF保护/重启方面存在缺陷，但在DSB修复方面表现出色。我们的数据表明，Ex27介导的RAD51细丝稳定对于RF保护是必需的，而对于DSB修复似乎是可有可无的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/4cde5ca338c3/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/5a40aafbb3bd/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/2180168256dc/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/15e4b511fca5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/fbb0e3206f45/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/0e204548be7d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/4cde5ca338c3/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/5a40aafbb3bd/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/2180168256dc/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/15e4b511fca5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/fbb0e3206f45/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/0e204548be7d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a92/10993188/4cde5ca338c3/gr5.jpg

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RAD51 bypasses the CMG helicase to promote replication fork reversal.RAD51 绕过 CMG 解旋酶以促进复制叉反转。
Science. 2023 Apr 28;380(6643):382-387. doi: 10.1126/science.add7328. Epub 2023 Apr 27.
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Activation of homologous recombination in G1 preserves centromeric integrity.在 G1 期激活同源重组可保持着丝粒的完整性。
Nature. 2021 Dec;600(7890):748-753. doi: 10.1038/s41586-021-04200-z. Epub 2021 Dec 1.
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TREX2 Exonuclease Causes Spontaneous Mutations and Stress-Induced Replication Fork Defects in Cells Expressing RAD51.TREX2 核酸外切酶导致表达 RAD51 的细胞中自发突变和应激诱导的复制叉缺陷。
Cell Rep. 2020 Dec 22;33(12):108543. doi: 10.1016/j.celrep.2020.108543.
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Single-molecule visualization of human RECQ5 interactions with single-stranded DNA recombination intermediates.人类RECQ5与单链DNA重组中间体相互作用的单分子可视化
Nucleic Acids Res. 2021 Jan 11;49(1):285-305. doi: 10.1093/nar/gkaa1184.
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