Human AAA+ ATPase FIGNL1 suppresses RAD51-mediated ultra-fine bridge formation.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Genomic Instability*/genetics ; Rad51 Recombinase*/metabolism ; Rad51 Recombinase*/genetics; Humans ; Chromatids/metabolism ; Chromatids/genetics ; DNA Replication/genetics ; Homologous Recombination/genetics ; Cell Line ; Gene Knockout Techniques

RAD51 filament is crucial for the homology-dependent repair of DNA double-strand breaks and stalled DNA replication fork protection. Positive and negative regulators control RAD51 filament assembly and disassembly. RAD51 is vital for genome integrity but excessive accumulation of RAD51 on chromatin causes genome instability and growth defects. However, the detailed mechanism underlying RAD51 disassembly by negative regulators and the physiological consequence of abnormal RAD51 persistence remain largely unknown. Here, we report the role of the human AAA+ ATPase FIGNL1 in suppressing a novel type of RAD51-mediated genome instability. FIGNL1 knockout human cells were defective in RAD51 dissociation after replication fork restart and accumulated ultra-fine chromosome bridges (UFBs), whose formation depends on RAD51 rather than replication fork stalling. FIGNL1 suppresses homologous recombination intermediate-like UFBs generated between sister chromatids at genomic loci with repeated sequences such as telomeres and centromeres. These data suggest that RAD51 persistence per se induces the formation of unresolved linkage between sister chromatids resulting in catastrophic genome instability. FIGNL1 facilitates post-replicative disassembly of RAD51 filament to suppress abnormal recombination intermediates and UFBs. These findings implicate FIGNL1 as a key factor required for active RAD51 removal after processing of stalled replication forks, which is essential to maintain genome stability.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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20K06604 Japan Society for the Promotion of Science; Takeda Science Foundation Kindai University

EC 2.7.7.- (RAD51 protein, human)
EC 2.7.7.- (Rad51 Recombinase)

Date Created: 20240410 Date Completed: 20240609 Latest Revision: 20240611

20240611

PMC11162793

10.1093/nar/gkae263

38597669