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 and Julian Stingele ()
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Pedro Weickert: Ludwig-Maximilians-University
Hao-Yi Li: Ludwig-Maximilians-University
Maximilian J. Götz: Ludwig-Maximilians-University
Sophie Dürauer: Ludwig-Maximilians-University
Denitsa Yaneva: Ludwig-Maximilians-University
Shubo Zhao: Ludwig-Maximilians-University
Jacqueline Cordes: Ludwig-Maximilians-University
Aleida C. Acampora: Ludwig-Maximilians-University
Ignasi Forne: Ludwig-Maximilians-University
Axel Imhof: Ludwig-Maximilians-University
Julian Stingele: Ludwig-Maximilians-University

Nature Communications, 2023, vol. 14, issue 1, 1-14

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.

Date: 2023
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DOI: 10.1038/s41467-023-35988-1

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