RNF4 prevents genomic instability caused by chronic DNA under-replication.

Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101139138 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1568-7856 (Electronic) Linking ISSN: 15687856 NLM ISO Abbreviation: DNA Repair (Amst) Subsets: MEDLINE

Original Publication: Amsterdam ; New York : Elsevier, c2002-

Genomic Instability* ; DNA Repair*; Humans ; DNA Replication ; Mitosis ; Saccharomyces cerevisiae/genetics ; Nuclear Proteins/genetics ; Transcription Factors

Eukaryotic genome stability is maintained by a complex and diverse set of molecular processes. One class of enzymes that promotes proper DNA repair, replication and cell cycle progression comprises small ubiquitin-like modifier (SUMO)-targeted E3 ligases, or STUbLs. Previously, we reported a role for the budding yeast STUbL synthetically lethal with sgs1 (Slx) 5/8 in preventing G 2 /M-phase arrest in a minichromosome maintenance protein 10 (Mcm10)-deficient model of replication stress. Here, we extend these studies to human cells, examining the requirement for the human STUbL RING finger protein 4 (RNF4) in MCM10 mutant cancer cells. We find that MCM10 and RNF4 independently promote origin firing but regulate DNA synthesis epistatically and, unlike in yeast, the negative genetic interaction between RNF4 and MCM10 causes cells to accumulate in G 1 -phase. When MCM10 is deficient, RNF4 prevents excessive DNA under-replication at hard-to-replicate regions that results in large DNA copy number alterations and severely reduced viability. Overall, our findings highlight that STUbLs participate in species-specific mechanisms to maintain genome stability, and that human RNF4 is required for origin activation in the presence of chronic replication stress.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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R01 GM134681 United States GM NIGMS NIH HHS; P30 CA077598 United States CA NCI NIH HHS; R01 GM074917 United States GM NIGMS NIH HHS; T32 CA009138 United States CA NCI NIH HHS; F30 CA257227 United States CA NCI NIH HHS; TL1 TR002493 United States TR NCATS NIH HHS; R35 GM141805 United States GM NIGMS NIH HHS

Keywords: Genome instability; MCM10; RNF4; Replication stress; Under-replicated DNA

0 (RNF4 protein, human)
0 (Nuclear Proteins)
0 (Transcription Factors)

Date Created: 20240210 Date Completed: 20240304 Latest Revision: 20240524

20240524

PMC10948022

10.1016/j.dnarep.2024.103646

38340377