8RS8

Crystal structure of BRCA1 BRCTs in complex with a RIF1 phosphopeptide

Summary for 8RS8

• Entry DOI: 10.2210/pdb8rs8/pdb
• Descriptor: Breast cancer type 1 susceptibility protein, Telomere-associated protein RIF1, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: dna damage repair, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 106671.98

Authors

Day, M.,Pearl, L.H.,Oliver, A.W. (deposition date: 2024-01-24, release date: 2025-07-16)

Primary citation

Dong, Q.,Day, M.,Saito, Y.,Parker, E.,Watts, L.P.,Kanemaki, M.T.,Oliver, A.W.,Pearl, L.H.,Hiraga, S.I.,Donaldson, A.D.
The human RIF1-Long isoform interacts with BRCA1 to promote recombinational fork repair under DNA replication stress.
Nat Commun, 16:5820-5820, 2025

PubMed 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.

PubMed: 40595496
DOI: 10.1038/s41467-025-60817-y

Experimental method

X-RAY DIFFRACTION (1.31 Å)