Abstract
RAD51 assembly on single-stranded (ss)DNAs is a crucial step in the homology-dependent repair of DNA damage for genomic stability. The formation of the RAD51 filament is promoted by various RAD51-interacting proteins including RAD51 paralogues. However, the mechanisms underlying the differential control of RAD51-filament dynamics by these factors remain largely unknown. Here, we report a role for the human RAD51 paralogue, SWSAP1, as a novel regulator of RAD51 assembly. Swsap1-deficient cells show defects in DNA damage-induced RAD51 assembly during both mitosis and meiosis. Defective RAD51 assembly in SWSAP1-depleted cells is suppressed by the depletion of FIGNL1, which binds to RAD51 as well as SWSAP1. Purified FIGNL1 promotes the dissociation of RAD51 from ssDNAs. The dismantling activity of FIGNL1 does not require its ATPase but depends on RAD51-binding. Purified SWSAP1 inhibits the RAD51-dismantling activity of FIGNL1. Taken together, our data suggest that SWSAP1 protects RAD51 filaments by antagonizing the anti-recombinase, FIGNL1.
Highlights
RAD51 assembly on single-strandedDNAs is a crucial step in the homology-dependent repair of DNA damage for genomic stability
We find that SWSAP1 interacts with Fidgetin-like 1 (FIGNL1), an AAA+ ATPase involved in HR29
We observed that the SWSAP1 N-terminus contains the FxxA motif, a highly conserved RAD51-binding motif[30], which was originally identified in BRC repeats of the BRCA2 protein, referred as to BRC variant (BRCv) (Fig. 1c)
Summary
RAD51 assembly on single-stranded (ss)DNAs is a crucial step in the homology-dependent repair of DNA damage for genomic stability. The formation of the RAD51 filament is promoted by various RAD51-interacting proteins including RAD51 paralogues. Purified FIGNL1 promotes the dissociation of RAD51 from ssDNAs. The dismantling activity of FIGNL1 does not require its ATPase but depends on RAD51-binding. Homologous recombination (HR) is essential to maintain genome stability by repairing DNA double-strand breaks (DSBs) and stalled DNA replication forks. In DSB repair, HR requires the formation of single-stranded DNA (ssDNA). The ssDNA is used to find a homologous double-stranded DNA (dsDNA) and invaded it to form a displacement loop called a D-. RAD51 loading on RPA-coated ssDNA, RAD51 requires positive regulators called RAD51 mediators that act to load RAD51 on the RPA-bound DNA. RAD51 mediators, which bind directly to RAD51, include the breast cancer susceptibility gene, BRCA2, as well as RAD52 and RAD51 paralogues[8]
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