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- W4317659311 abstract "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." @default.
- W4317659311 created "2023-01-21" @default.
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- W4317659311 date "2023-01-21" @default.
- W4317659311 modified "2023-10-16" @default.
- W4317659311 title "SPRTN patient variants cause global-genome DNA-protein crosslink repair defects" @default.
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- W4317659311 doi "https://doi.org/10.1038/s41467-023-35988-1" @default.
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