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

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 Tomida, Jessica L. Bowser and Cyrus Vaziri ()
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Lilly F. Chiou: University of North Carolina at Chapel Hill
Gaith N. Droby: University of North Carolina at Chapel Hill
Deepika Jayaprakash: University of North Carolina at Chapel Hill
Jay R. Anand: University of North Carolina at Chapel Hill
Xingyuan Zhang: University of North Carolina at Chapel Hill
Yang Yang: University of North Carolina at Chapel Hill
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
Cyrus Vaziri: University of North Carolina at Chapel Hill

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62368-8

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