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

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. Cesare, Alexander P. Sobinoff and Hilda A. Pickett ()
Additional contact information
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
Anthony J. Cesare: University of Sydney
Alexander P. Sobinoff: University of Sydney
Hilda A. Pickett: University of Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46578-0

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