Carver Alexander, Yu Tai-Yuan, Yates Luke A, White Travis, Wang Raymond, Lister Katie, Jasin Maria, Zhang Xiaodong
DNA Processing Machines Laboratory, Francis Crick Institute, London, UK.
Section of Structural and Synthetic Biology, Department of Infectious Disease, Imperial College London, London, UK.
Science. 2025 Jan 24;387(6732):426-431. doi: 10.1126/science.adr7920. Epub 2024 Dec 5.
Maintaining genome integrity is an essential and challenging process. RAD51 recombinase, the central component of several crucial processes in repairing DNA and protecting genome integrity, forms filaments on DNA, which are tightly regulated. One of these RAD51 regulators is FIGNL1 (fidgetin-like 1), which prevents RAD51 genotoxic chromatin association in normal cells and persistent RAD51 foci upon DNA damage. The cryogenic electron microscopy-imaged structure of FIGNL1 in complex with RAD51 reveals that FIGNL1 forms a nonplanar hexamer and encloses RAD51 N terminus in the FIGNL1 hexamer pore. Mutations in pore loop or catalytic residues of FIGNL1 render it defective in filament disassembly and are lethal in mouse embryonic stem cells. Our study reveals a distinct mechanism for removing RAD51 from bound substrates and provides the molecular basis for FIGNL1 in maintaining genome stability.
维持基因组完整性是一个至关重要且具有挑战性的过程。RAD51重组酶是修复DNA和保护基因组完整性的几个关键过程的核心组成部分，它在DNA上形成细丝，且受到严格调控。其中一种RAD51调节剂是FIGNL1（类fidgetin 1），它可防止正常细胞中RAD51与基因毒性染色质结合以及DNA损伤后持续性RAD51病灶的形成。与RAD51复合物的低温电子显微镜成像结构显示，FIGNL1形成一个非平面六聚体，并将RAD51 N端包围在FIGNL1六聚体孔中。FIGNL1孔环或催化残基的突变使其在细丝解聚方面存在缺陷，并在小鼠胚胎干细胞中具有致死性。我们的研究揭示了一种从结合底物中去除RAD51的独特机制，并为FIGNL1维持基因组稳定性提供了分子基础。
