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

Abstract

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 FIGNL1-FIRRM complex is required to complete meiotic recombination in the mouse and prevents massive DNA damage-independent RAD51 and DMC1 loading

“…were identified recently as negative regulators of meiotic COs in plants 44,[52][53][54] , and as negative regulators of RAD51 in human cells 40,43,[47][48][49][50]57,80 . However, their role in mammalian meiosis remained unknown, although a role for Fignl1 was hypothesized in mouse male meiosis 81 .…”

“…The SWSAP1-SWS1-SPIDR complex might promote specifically the stable assembly of longer RAD51 nucleoprotein filaments involved in some HR types, especially interhomolog HR 36,37 . FIGNL1 (fidgetin-like 1) forms an evolutionary conserved complex with FIRRM (FIGNL1 interacting regulator of recombination and mitosis) that interacts with RAD51 and DMC1, and regulates negatively RAD51 during HR repair in mammalian cells [43][44][45][46][47][48][49][50][51] . In Arabidopsis and rice meiosis, FIGNL1 and FIRRM homologs negatively regulate the dynamics of RAD51 and DMC1 foci and limit the formation of class II crossovers 44,45,[52][53][54] .…”