Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway
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- Mechanism and function of DNA replicationindependent DNA-protein crosslink repair via the SUMO-RNF4 pathway
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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.
Originalsprog | Engelsk |
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Artikelnummer | e107413 |
Tidsskrift | E M B O Journal |
Vol/bind | 40 |
Antal sider | 21 |
ISSN | 0261-4189 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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