期刊
MOLECULAR CELL
卷 81, 期 5, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.12.020
关键词
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资金
- Francis Crick Institute from Cancer Research UK [FC0010048]
- UK Medical Research Council [FC0010048]
- Wellcome Trust [FC0010048]
- Wellcome Trust
- Wellcome Trust collaborative grant [P67153]
- MRC-London Institute of Medical Sciences [UKRI MC-A6585TY10]
- BBSRC CASE-studentship
- MRC [M-A652-5PY60]
- European Research Council (ERC) advanced investigator (TelMetab) grant
- MRC [MC_U120097113, MC_UP_1102/5] Funding Source: UKRI
Homologous recombination (HR) is a crucial DNA repair mechanism that is often disrupted in cancer, with RAD51 playing a key role in this process. Employing single-molecule imaging, the study investigated the mechanism of RAD-51 nucleation and filament growth in the presence of recombination mediators BRC-2 and RAD-51 paralogs RFS-1/RIP-1. The findings revealed that BRC-2 initiates RAD-51 nucleation on RPA-coated DNA, while RFS-1/RIP-1 acts as a chaperone to promote filament growth by dynamically engaging with filament ends.
Homologous recombination (HR) is an essential DNA double-strand break (DSB) repair mechanism, which is frequently inactivated in cancer. During HR, RAD51 forms nucleoprotein filaments on RPA-coated, resected DNA and catalyzes strand invasion into homologous duplex DNA. How RAD51 displaces RPA and assembles into long HR-proficient filaments remains uncertain. Here, we employed single-molecule imaging to investigate the mechanism of nematode RAD-51 filament growth in the presence of BRC-2 (BRCA2) and RAD-51 paralogs, RFS-1/RIP-1. BRC-2 nucleates RAD-51 on RPA-coated DNA, whereas RFS-1/RIP-1 acts as a chaperone'' to promote 3' to 5' filament growth via highly dynamic engagement with 50 filament ends. Inhibiting ATPase or mutation in the RFS-1 Walker box leads to RFS-1/RIP-1 retention on RAD-51 filaments and hinders growth. The rfs-1 Walker box mutants display sensitivity to DNA damage and accumulate RAD-51 complexes non-functional for HR in vivo. Our work reveals the mechanism of RAD-51 nucleation and filament growth in the presence of recombination mediators.
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