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

Author

Listed:
  • Pedro Weickert

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Hao-Yi Li

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Maximilian J. Götz

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Sophie Dürauer

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Denitsa Yaneva

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Shubo Zhao

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Jacqueline Cordes

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Aleida C. Acampora

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

  • Ignasi Forne

    (Ludwig-Maximilians-University)

  • Axel Imhof

    (Ludwig-Maximilians-University)

  • Julian Stingele

    (Ludwig-Maximilians-University
    Ludwig-Maximilians-University)

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.

Suggested Citation

  • 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. "SPRTN patient variants cause global-genome DNA-protein crosslink repair defects," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35988-1
    DOI: 10.1038/s41467-023-35988-1
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    References listed on IDEAS

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