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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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  • Qianqian Dong

    (University of Aberdeen)

  • Matthew Day

    (University of Sussex
    Queen Mary University of London)

  • Yuichiro Saito

    (Research Organization of Information and Systems (ROIS)
    Memorial Sloan Kettering Cancer Center and Howard Hughes Medical Institute)

  • Emma Parker

    (University of Aberdeen)

  • Lotte P. Watts

    (University of Aberdeen
    University of Colorado-Boulder)

  • Masato T. Kanemaki

    (Research Organization of Information and Systems (ROIS)
    SOKENDAI
    The University of Tokyo)

  • Antony W. Oliver

    (University of Sussex)

  • Laurence H. Pearl

    (University of Sussex
    Chester Beatty Laboratories)

  • Shin-ichiro Hiraga

    (University of Aberdeen)

  • Anne D. Donaldson

    (University of Aberdeen)

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.

Suggested Citation

  • Qianqian Dong & Matthew Day & Yuichiro Saito & Emma Parker & Lotte P. Watts & Masato T. Kanemaki & Antony W. Oliver & Laurence H. Pearl & Shin-ichiro Hiraga & Anne D. Donaldson, 2025. "The human RIF1-Long isoform interacts with BRCA1 to promote recombinational fork repair under DNA replication stress," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60817-y
    DOI: 10.1038/s41467-025-60817-y
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