SPRTN protease and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability
SPRTN protease and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability
Abstract DNA-protein crosslinks (DPCs) are a specific type of DNA lesions where proteins are covalently attached to DNA. Unrepaired DPCs lead to genomic instability, cancer, neurodegeneration and accelerated ageing. DPC proteolysis was recently discovered as a specialised pathway for DPC repair. The DNA-dependent SPRTN protease and 26S proteasome emerged as as two independent proteolytic systems for DPC repair. DPCs are also repaired by homologous recombination (HR), a canonical DNA repair pathway. While studying the role of ubiquitin and SUMO in DPC repair, we identified mutually exclusive signalling mechanisms associated with DPC repair pathway choice. DPC modification by SUMO-1 favours SPRTN proteolysis as the preferred pathway for DPC repair. DPC SUMOylation counteracts DPC ubiquitination, which promotes DNA breaks and the switch to HR. We propose that modification of DPCs by SUMO-1 promotes SPRTN proteolysis, which is essential for DPC removal to prevent DNA replication defects, chromosomal recombination and genomic instability.
Vaz Bruno、Kilgas Susan、Singh Abhay N.、Ruggiano Annamaria、Kiltie Anne E.、Popovic Marta、Higgins Geoffrey S.、Ramadan Kristijan、Rodriguez-Berriguete Gonzalo
Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of OxfordCancer Research UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford
分子生物学遗传学生物化学
Vaz Bruno,Kilgas Susan,Singh Abhay N.,Ruggiano Annamaria,Kiltie Anne E.,Popovic Marta,Higgins Geoffrey S.,Ramadan Kristijan,Rodriguez-Berriguete Gonzalo.SPRTN protease and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/2020.02.14.949289.点此复制
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