Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway
| Autor: | Ulrike Kühbacher, Irene Gallina, Julio C Y Liu, Yoshiaki Azuma, Nicolai B. Larsen, Claire Guérillon, Nikoline Borgermann, Niels Mailand, Ronald T. Hay, Emma Branigan, Leena Ackermann, Dimitriya H Garvanska, Ivo A. Hendriks, Michael L. Nielsen, Peter Haahr, Julien P. Duxin |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
DNA Repair DNA repair SUMO protein General Biochemistry Genetics and Molecular Biology Genomic Instability Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ubiquitin Humans Molecular Biology Mitosis 030304 developmental biology 0303 health sciences General Immunology and Microbiology biology General Neuroscience DNA replication Ubiquitination Nuclear Proteins Sumoylation DNA Replication Repair & Recombination Post-translational Modifications Proteolysis & Proteomics Articles Ubiquitin ligase Cell biology DNA‐protein crosslinks chemistry Proteasome SUMO embryonic structures biology.protein Small Ubiquitin-Related Modifier Proteins Protein Processing Post-Translational 030217 neurology & neurosurgery DNA genome stability Protein Binding Signal Transduction Transcription Factors |
| Zdroj: | Liu, J C Y, Kühbacher, U, Larsen, N B, Borgermann, N, Garvanska, D H, Hendriks, I A, Ackermann, L, Haahr, P, Gallina, I, Guérillon, C, Branigan, E, Hay, R T, Azuma, Y, Nielsen, M L, Duxin, J P & Mailand, N 2021, ' Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway ', E M B O Journal, vol. 40, e107413 . https://doi.org/10.15252/embj.2020107413 The EMBO Journal |
| DOI: | 10.15252/embj.2020107413 |
| Popis: | 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. SUMOylation‐dependent ubiquitylation mediates an important salvage pathway for premitotic resolution of DNA‐protein crosslinks on duplex DNA, which do not trigger interphase DNA damage checkpoints. |
| Databáze: | OpenAIRE |
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