Yang Sile F, Nelson Christopher B, Wells Jadon K, Fernando Madushan, Lu Robert, Allen Joshua A M, Malloy Lisa, Lamm Noa, Murphy Vincent J, Mackay Joel P, Deans Andrew J, Cesare Anthony J, Sobinoff Alexander P, Pickett Hilda A
Telomere Length Regulation Unit, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, 2145, Australia.
Nuclear Dynamics Group, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, 2145, Australia.
Nat Commun. 2024 Mar 12;15(1):2210. doi: 10.1038/s41467-024-46578-0.
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.
ATR-CHK1 DNA损伤反应通路通过暴露RPA包被的单链DNA（ssDNA）而被激活，RPA包被的ssDNA是DNA损伤和修复过程中的中间体，也是复制应激反应的一部分。在此，我们鉴定出ZNF827是ATR-CHK1激酶通路的一个组成部分。我们证明ZNF827是一种ssDNA结合蛋白，通过与ssDNA中间体同时结合而与RPA相互作用。这些相互作用依赖于ZNF827内的两簇C2H2锌指基序。我们发现ZNF827在停滞的复制叉和DNA损伤位点积累，在那里它激活ATR并促进同源重组介导的DNA修复。此外，我们证明ZNF827的缺失会抑制复制起始并使癌细胞对拓扑异构酶抑制剂拓扑替康敏感，这表明ZNF827是DNA损伤反应通路中的一个治疗靶点。
