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ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway

Author

Listed:
  • Sile F. Yang

    (University of Sydney)

  • Christopher B. Nelson

    (University of Sydney)

  • Jadon K. Wells

    (University of Sydney)

  • Madushan Fernando

    (University of Sydney)

  • Robert Lu

    (University of Sydney)

  • Joshua A. M. Allen

    (University of Sydney)

  • Lisa Malloy

    (University of Sydney)

  • Noa Lamm

    (University of Sydney)

  • Vincent J. Murphy

    (St Vincent’s Institute)

  • Joel P. Mackay

    (University of Sydney)

  • Andrew J. Deans

    (St Vincent’s Institute
    University of Melbourne)

  • Anthony J. Cesare

    (University of Sydney)

  • Alexander P. Sobinoff

    (University of Sydney)

  • Hilda A. Pickett

    (University of Sydney)

Abstract

The ATR-CHK1 DNA damage response pathway becomes activated by the exposure of RPA-coated single-stranded DNA (ssDNA) that forms as an intermediate during DNA damage and repair, and as a part of the replication stress response. Here, we identify ZNF827 as a component of the ATR-CHK1 kinase pathway. We demonstrate that ZNF827 is a ssDNA binding protein that associates with RPA through concurrent binding to ssDNA intermediates. These interactions are dependent on two clusters of C2H2 zinc finger motifs within ZNF827. We find that ZNF827 accumulates at stalled forks and DNA damage sites, where it activates ATR and promotes the engagement of homologous recombination-mediated DNA repair. Additionally, we demonstrate that ZNF827 depletion inhibits replication initiation and sensitizes cancer cells to the topoisomerase inhibitor topotecan, revealing ZNF827 as a therapeutic target within the DNA damage response pathway.

Suggested Citation

  • Sile F. Yang & Christopher B. Nelson & Jadon K. Wells & Madushan Fernando & Robert Lu & Joshua A. M. Allen & Lisa Malloy & Noa Lamm & Vincent J. Murphy & Joel P. Mackay & Andrew J. Deans & Anthony J. , 2024. "ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46578-0
    DOI: 10.1038/s41467-024-46578-0
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