Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway.
DNA repair
DNA-protein crosslinks
SUMO
genome stability
ubiquitin
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
15 09 2021
15 09 2021
Historique:
revised:
03
07
2021
received:
29
11
2020
accepted:
12
07
2021
pubmed:
5
8
2021
medline:
15
12
2021
entrez:
4
8
2021
Statut:
ppublish
Résumé
DNA-protein crosslinks (DPCs) obstruct essential DNA transactions, posing a serious threat to genome stability and functionality. DPCs are proteolytically processed in a ubiquitin- and DNA replication-dependent manner by SPRTN and the proteasome but can also be resolved via targeted SUMOylation. However, the mechanistic basis of SUMO-mediated DPC resolution and its interplay with replication-coupled DPC repair remain unclear. Here, we show that the SUMO-targeted ubiquitin ligase RNF4 defines a major pathway for ubiquitylation and proteasomal clearance of SUMOylated DPCs in the absence of DNA replication. Importantly, SUMO modifications of DPCs neither stimulate nor inhibit their rapid DNA replication-coupled proteolysis. Instead, DPC SUMOylation provides a critical salvage mechanism to remove DPCs formed after DNA replication, as DPCs on duplex DNA do not activate interphase DNA damage checkpoints. Consequently, in the absence of the SUMO-RNF4 pathway cells are able to enter mitosis with a high load of unresolved DPCs, leading to defective chromosome segregation and cell death. Collectively, these findings provide mechanistic insights into SUMO-driven pathways underlying replication-independent DPC resolution and highlight their critical importance in maintaining chromosome stability and cellular fitness.
Identifiants
pubmed: 34346517
doi: 10.15252/embj.2020107413
pmc: PMC8441304
doi:
Substances chimiques
Nuclear Proteins
0
RNF4 protein, human
0
Small Ubiquitin-Related Modifier Proteins
0
Transcription Factors
0
Ubiquitin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e107413Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C434/A21747
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 217196/Z/19/Z
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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