Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway.
EMBO J
; 40(18): e107413, 2021 09 15.
Article
in En
| MEDLINE
| ID: mdl-34346517
ABSTRACT
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Transcription Factors
/
Nuclear Proteins
/
Signal Transduction
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Small Ubiquitin-Related Modifier Proteins
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DNA Repair
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DNA Replication
Limits:
Humans
Language:
En
Year:
2021
Type:
Article