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.
bioRxiv. 2024 Jul 16:2024.07.16.603765. doi: 10.1101/2024.07.16.603765.
Maintaining genome integrity is an essential and challenging process. RAD51 recombinase, the central player of several crucial processes in repairing and protecting genome integrity, forms filaments on DNA. RAD51 filaments are tightly regulated. One of these regulators is FIGNL1, that prevents persistent RAD51 foci post-damage and genotoxic chromatin association in cells. The cryogenic electron microscopy structure of FIGNL1 in complex with RAD51 reveals that the FIGNL1 forms a non-planar hexamer and RAD51 N-terminus is enclosed 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 unique mechanism for removing RAD51 from DNA 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重组酶是修复和保护基因组完整性的几个关键过程的核心参与者，它在DNA上形成细丝。RAD51细丝受到严格调控。其中一种调节因子是FIGNL1，它可防止细胞损伤后持续存在的RAD51病灶以及基因毒性染色质关联。FIGNL1与RAD51复合物的低温电子显微镜结构显示，FIGNL1形成非平面六聚体，RAD51的N端被封闭在FIGNL1六聚体孔中。FIGNL1孔环或催化残基的突变使其在细丝拆卸方面存在缺陷，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DNA上去除RAD51的独特机制，并为FIGNL1维持基因组稳定性提供了分子基础。
