Publication of IMPRS-LS student Pedro Weickert

Weickert, P.^#, Li, H.Y.^#, Götz, M.J., Dürauer, S., Yaneva, D., Zhao, S., Cordes, J., Acampora, A.C., Forne, I., Imhof, A., and Stingele, J.
(IMPRS-LS students are in bold) ^#equal contribution
Nat Commun, 2023, 14, 352.
doi: 10.1038/s41467-023-35988-1

SPRTN patient variants cause global-genome DNA-protein crosslink repair defects

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.