RNF4 and USP7 cooperate in ubiquitin-regulated steps of DNA replication

DNA replication requires precise regulation achieved through post-translational modifications, including ubiquitination and SUMOylation. These modifications are linked by the SUMO-targeted E3 ubiquitin ligases (STUbLs). Ring finger protein 4 (RNF4), one of only two mammalian STUbLs, participates in...

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Bibliographic Details
Published in:Open biology 2023-08, Vol.13 (8), p.230068-230068
Main Authors: Chang, Ya-Chu, Lin, Kevin, Baxley, Ryan M, Durrett, Wesley, Wang, Liangjun, Stojkova, Olivera, Billmann, Maximilian, Ward, Henry, Myers, Chad L, Bielinsky, Anja-Katrin
Format: Article
Language:English
Subjects:
Animals
DNA Replication
genome stability
Mammals
Protein Processing, Post-Translational
RNF4
STUbL
SUMO
Ubiquitin
Ubiquitin-Specific Peptidase 7 - genetics
Ubiquitination
USP7
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Summary:DNA replication requires precise regulation achieved through post-translational modifications, including ubiquitination and SUMOylation. These modifications are linked by the SUMO-targeted E3 ubiquitin ligases (STUbLs). Ring finger protein 4 (RNF4), one of only two mammalian STUbLs, participates in double-strand break repair and resolving DNA-protein cross-links. However, its role in DNA replication has been poorly understood. Using CRISPR/Cas9 genetic screens, we discovered an unexpected dependency of mutants on ( for survival in -null retinal pigment epithelial cells. triple knockout (TKO) cells displayed defects in DNA replication that cause genomic instability. These defects were exacerbated by the proteasome inhibitor bortezomib, which limited the nuclear ubiquitin pool. A shortage of free ubiquitin suppressed the ataxia telangiectasia and Rad3-related (ATR)-mediated checkpoint response, leading to increased cell death. In conclusion, RNF4 and USP7 work cooperatively to sustain a functional level of nuclear ubiquitin to maintain the integrity of the genome.
ISSN:2046-2441
2046-2441
DOI:10.1098/rsob.230068