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Weickert, Pedro; Li, Hao-Yi; Götz, Maximilian J.; Dürauer, Sophie; Yaneva, Denitsa; Zhao, Shubo; Cordes, Jacqueline; Acampora, Aleida C.; Forne, Ignasi; Imhof, Axel; Stingele, Julian (2023): SPRTN patient variants cause global-genome DNA-protein crosslink repair defects. Nature Communications, 14 (1). ISSN 2041-1723

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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.

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