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Cited by 4DNA Repair MechanismsBRCA gene mutations in cancerPARP inhibition in cancer therapy

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The human RIF1-Long isoform interacts with BRCA1 to promote recombinational fork repair under DNA replication stress

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Dong, Qianqian, Day, Matthew, Saito, Yuichiro, Parker, Emma, Watts, Lotte P., Kanemaki, Masato T., Oliver, Antony W., Pearl, Laurence H., Hiraga, Shin-ichiro, Donaldson, Anne D.·2025·Nature Communications
DOI 10.1038/s41467-025-60817-yPMC PMC12214830

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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.

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Metadata

Authors
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.
Affiliations
  • University of Aberdeen (GB)
  • University of Sussex (GB)
  • National Institute of Genetics (JP)
  • University of Colorado Boulder (US)
  • Institute of Cancer Research (GB)
Corresponding author
  • Hiraga, Shin-ichiro
  • Donaldson, Anne D.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-07-01
Volume
16
Issue
1
Pages
5820-5820
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-60817-y
PMC
PMC12214830
OpenAlex
W4411885443
Cited by
4
References
1
Citations by year
2026: 1 · 2025: 2
FWCI
0.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Cancer Research UK (C1445/A19059, DRCPGM\100013, C302/A24386)
  • MEXT | Japan Society for the Promotion of Science (JP21H0419, JP23H04925)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords
BRCA1, BRCT domain, replication stress, RAD51 foci, ATR signaling, S phase, alternative splicing, DNA replication
MeSH terms
DNA Repair, DNA Replication, Humans, Phosphorylation, Protein Binding, BRCA1 Protein, Protein Isoforms, Telomere-Binding Proteins, Cell Line, Tumor, Rad51 Recombinase, HEK293 Cells, Recombinational DNA Repair, Ataxia Telangiectasia Mutated Proteins

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