{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Weickert P"],"funding":["European Research Council","Deutsche Forschungsgemeinschaft (German Research Foundation)","European Molecular Biology Organization (EMBO)","Alfried Krupp von Bohlen und Halbach-Stiftung (Alfried Krupp von Bohlen und Halbach Foundation)"],"pagination":["352"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9867749"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14(1)"],"pubmed_abstract":["DNA-protein crosslinks (DPCs) are pervasive DNA lesions that are induced by reactive metabolites and various chemotherapeutic agents. Here, we develop a technique for the Purification of x-linked Proteins (PxP), which allows identification and tracking of diverse DPCs in mammalian cells. Using PxP, we investigate DPC repair in cells genetically-engineered to express variants of the SPRTN protease that cause premature ageing and early-onset liver cancer in Ruijs-Aalfs syndrome patients. We find an unexpected role for SPRTN in global-genome DPC repair, that does not rely on replication-coupled detection of the lesion. Mechanistically, we demonstrate that replication-independent DPC cleavage by SPRTN requires SUMO-targeted ubiquitylation of the protein adduct and occurs in addition to proteasomal DPC degradation. Defective ubiquitin binding of SPRTN patient variants compromises global-genome DPC repair and causes synthetic lethality in combination with a reduction in proteasomal DPC repair capacity."],"journal":["Nature communications"],"pubmed_title":["SPRTN patient variants cause global-genome DNA-protein crosslink repair defects."],"pmcid":["PMC9867749"],"funding_grant_id":["801750","Alfried Krupp Prize","YIP4644","Project ID 213249687 - SFB 1064"],"pubmed_authors":["Weickert P","Gotz MJ","Forne I","Zhao S","Durauer S","Imhof A","Stingele J","Li HY","Acampora AC","Cordes J","Yaneva D"],"additional_accession":[]},"is_claimable":false,"name":"SPRTN patient variants cause global-genome DNA-protein crosslink repair defects.","description":"DNA-protein crosslinks (DPCs) are pervasive DNA lesions that are induced by reactive metabolites and various chemotherapeutic agents. Here, we develop a technique for the Purification of x-linked Proteins (PxP), which allows identification and tracking of diverse DPCs in mammalian cells. Using PxP, we investigate DPC repair in cells genetically-engineered to express variants of the SPRTN protease that cause premature ageing and early-onset liver cancer in Ruijs-Aalfs syndrome patients. We find an unexpected role for SPRTN in global-genome DPC repair, that does not rely on replication-coupled detection of the lesion. Mechanistically, we demonstrate that replication-independent DPC cleavage by SPRTN requires SUMO-targeted ubiquitylation of the protein adduct and occurs in addition to proteasomal DPC degradation. Defective ubiquitin binding of SPRTN patient variants compromises global-genome DPC repair and causes synthetic lethality in combination with a reduction in proteasomal DPC repair capacity.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2025-04-27T01:41:01.812Z","creation":"2025-02-19T03:00:22.929Z"},"accession":"S-EPMC9867749","cross_references":{"pubmed":["36681662"],"doi":["10.1038/s41467-023-35988-1"]}}