SPRTN patient variants cause global-genome DNA-protein crosslink repair defects
Pedro Weickert, Hao-Yi Li, Maximilian J. Götz, Sophie Dürauer, Denitsa Yaneva, Shubo Zhao, Jacqueline Cordes, Aleida C. Acampora, Ignasi Forne, Axel Imhof & Julian Stingele (2023 Jan 10) SPRTN patient variants cause global-genome DNA-protein crosslink repair defects. Nature Communications 14:352. https://doi.org/10.1038/s41467-023-35988-1
Abstract cited from the article:
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 globalgenome 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.