RNF4 and USP7 Cooperate in Ubiquitin-regulated Steps of DNA Replication

Overview

Journal Open Biol

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Aug 22

PMID 37607592

Authors

Ya-Chu Chang

Kevin Lin

Ryan M Baxley

Wesley Durrett

Liangjun Wang

Olivera Stojkova

Maximilian Billmann

Henry Ward

Chad L Myers

Anja-Katrin Bielinsky

Affiliations

Soon will be listed here.

Abstract

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.

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

Chang Y, Lin K, Baxley R, Durrett W, Wang L, Stojkova O Open Biol. 2023; 13(8):230068.

PMID: 37607592 PMC: 10444366. DOI: 10.1098/rsob.230068.

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