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Mechanism and function of DNA replication‐independent DNA‐protein crosslink repair via the SUMO‐RNF4 pathway
Author(s) -
Liu Julio C Y,
Kühbacher Ulrike,
Larsen Nicolai B,
Borgermann Nikoline,
Garvanska Dimitriya H,
Hendriks Ivo A,
Ackermann Leena,
Haahr Peter,
Gallina Irene,
Guérillon Claire,
Branigan Emma,
Hay Ronald T,
Azuma Yoshiaki,
Nielsen Michael Lund,
Duxin Julien P,
Mailand Niels
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020107413
Subject(s) - biology , dna , dna replication , replication protein a , mechanism (biology) , genetics , microbiology and biotechnology , control of chromosome duplication , dna repair , dna replication factor cdt1 , pre replication complex , dna binding protein , gene , transcription factor , philosophy , epistemology
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.