DNA-damage dependent isoform switching modulates RIF1 DNA repair complex assembly and phase separation.

ABSTRACT: How RIF1 (RAP1 interacting factor) fulfills its diverse roles in DNA double-strand break (DSB) repair, DNA replication, and nuclear organization remains elusive. Here we show that alternative splicing (AS) of a cassette exon (Ex32) encoding a Ser/Lys-rich (S/K) cassette in the RIF1 C-terminal domain (CTD) gives rise to RIF1-Long (RIF1-L) and RIF1-Short (RIF1-S) isoforms with different functional characteristics. We demonstrate that RIF1-Ex32 splice-in is mediated by an exonic splicing enhancer that is recognized by the splicing factor SRSF1 and antagonized by splicing inhibitors SRSF3 and SRSF7. Exposure to DNA damage inhibited Ex32 splice-in, potentiated the association of SRSF3 and SRSF7 with RIF1 pre-mRNA, and caused an increase in RIF1-S protein expression, which was also observed acro

SUBMITTER: Koo AS 

PROVIDER: S-EPMC11565852 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature