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The RING finger E3 ligase RNF25 protects DNA replication forks independently of its canonical roles in ubiquitin signaling

Author

Listed:
  • Lilly F. Chiou

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Gaith N. Droby

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Deepika Jayaprakash

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    Vanderbilt University School of Medicine)

  • Jay R. Anand

    (University of North Carolina at Chapel Hill)

  • Xingyuan Zhang

    (University of North Carolina at Chapel Hill
    Duke University)

  • Yang Yang

    (University of North Carolina at Chapel Hill
    National Institute of Environmental Health Sciences, National Institutes of Health)

  • C. Allie Mills

    (University of North Carolina at Chapel Hill)

  • Thomas S. Webb

    (University of North Carolina at Chapel Hill)

  • Natalie K. Barker

    (University of North Carolina at Chapel Hill)

  • Jialiu Xie

    (University of North Carolina at Chapel Hill)

  • Di Wu

    (University of North Carolina at Chapel Hill)

  • Laura E. Herring

    (University of North Carolina at Chapel Hill)

  • Junya Tomida

    (University of North Carolina at Charlotte)

  • Jessica L. Bowser

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Cyrus Vaziri

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

Abstract

The DNA damage response (DDR) mechanisms that allow cells to tolerate DNA replication stress are critically important for genome stability and cell viability. Using an unbiased genetic screen, we identify a role for the RING finger E3 ubiquitin ligase RNF25 in promoting DNA replication stress tolerance. In response to DNA replication stress, RNF25-deficient cells generate aberrantly high levels of single-stranded DNA (ssDNA), accumulate in S-phase and show reduced mitotic entry. Using single-molecule DNA fiber analysis, we show that RNF25 protects reversed DNA replication forks generated by the fork remodeler HLTF from nucleolytic degradation by MRE11 and CtIP. Mechanistically, RNF25 interacts with the replication fork protection factor REV7 and recruits REV7 to nascent DNA after replication stress. The role of RNF25 in protecting replication forks is fully separable from its canonical functions in ubiquitin conjugation. This work reveals the RNF25-REV7 signaling axis as an important protective mechanism in cells experiencing replication stress.

Suggested Citation

  • Lilly F. Chiou & Gaith N. Droby & Deepika Jayaprakash & Jay R. Anand & Xingyuan Zhang & Yang Yang & C. Allie Mills & Thomas S. Webb & Natalie K. Barker & Jialiu Xie & Di Wu & Laura E. Herring & Junya , 2025. "The RING finger E3 ligase RNF25 protects DNA replication forks independently of its canonical roles in ubiquitin signaling," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62368-8
    DOI: 10.1038/s41467-025-62368-8
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