The human RIF1-Long isoform interacts with BRCA1 to promote recombinational fork repair under DNA replication stress.
Loading...
Embargo End Date
ICR Authors
Authors
Dong, Q
Day, M
Saito, Y
Parker, E
Watts, LP
Kanemaki, MT
Oliver, AW
Pearl, LH
Hiraga, S-I
Donaldson, AD
Day, M
Saito, Y
Parker, E
Watts, LP
Kanemaki, MT
Oliver, AW
Pearl, LH
Hiraga, S-I
Donaldson, AD
Document Type
Journal Article
Date
2025-07-01
Date Accepted
2025-06-03
Abstract
RIF1 is a multifunctional protein that regulates DNA replication and repair. RIF1-deficient cells are hypersensitive to DNA replication stress. Of the two alternatively spliced RIF1 isoforms, called RIF1-Short and RIF1-Long, the RIF1-Long isoform is more capable than RIF1-Short in supporting cell recovery from replication stress. Examining replication stress resistance mechanisms specific to RIF1-Long, we find that prolonged replication stress unexpectedly induces interaction of RIF1-Long with BRCA1. Mechanistically, a phosphorylated SPKF motif unique to the RIF1-Long isoform binds the tandem BRCT domain of BRCA1. BRCA1-RIF1-Long interaction is strongly down-regulated through dephosphorylation by RIF1-associated Protein Phosphatase 1. BRCA1-RIF1-Long interaction requires ATR signaling, and occurs predominantly during S phase. Loss of RIF1-Long impairs the formation of RAD51 foci, and reduces the efficiency of homology-mediated repair at broken replication forks. In summary, our investigation establishes RIF1-Long as a new functional binding partner of the BRCA1-BRCT domain, crucial to protect cells from extended DNA replication stress by enabling RAD51-dependent repair of broken replication forks.
Citation
Nature Communications, 2025, 16 (1), pp. 5820 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Directorate Struct Biol