Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway

Julio C. Y. Liu, Ulrike Kühbacher, Nicolai B. Larsen, Nikoline Borgermann, Dimitriya H. Garvanska, Ivo A. Hendriks, Leena Ackermann, Peter Haahr, Irene Gallina, Claire Guérillon, Emma Branigan, Ronald T. Hay, Yoshiaki Azuma, Michael Lund Nielsen, Julien P. Duxin (Lead / Corresponding author), Niels Mailand (Lead / Corresponding author)

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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.

Original languageEnglish
Article numbere107413
Number of pages21
JournalThe EMBO Journal
Early online date4 Aug 2021
DOIs
Publication statusE-pub ahead of print - 4 Aug 2021

Keywords

  • DNA repair
  • DNA-protein crosslinks
  • SUMO
  • genome stability
  • ubiquitin

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