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

Julio C Y LiuUlrike KühbacherNicolai B LarsenNikoline BorgermannDimitriya H GarvanskaIvo A HendriksLeena AckermannPeter HaahrIrene GallinaClaire GuérillonEmma BraniganRonald Thomas HayYoshiaki AzumaMichael Lund NielsenJulien P DuxinNiels Mailand
Published in: The EMBO journal (2021)
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.
Keyphrases
  • single molecule
  • circulating tumor
  • cell free
  • dna damage
  • cell death
  • induced apoptosis
  • cell cycle arrest
  • cancer therapy
  • dna methylation
  • body composition
  • copy number
  • gene expression
  • genome wide