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Dürauer, S.* ; Kang, H.-S. ; Wiebeler, C.* ; Machida, Y.* ; Schnapka, D.S.* ; Yaneva, D.* ; Renz, C.* ; Götz, M.J.* ; Weickert, P.* ; Major, A.C.* ; Rahmanto, A.S.* ; Gutenthaler-Tietze, S.M.* ; Daumann, L.J.* ; Beli, P.* ; Ulrich, H.D.* ; Sattler, M. ; Machida, Y.J.* ; Schwierz, N.* ; Stingele, J.*

Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability.

Nat. Commun. 16:5422 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslinks (DPCs). To understand how SPRTN's promiscuous protease activity is confined to cleavage of crosslinked proteins, we reconstitute the repair of DPCs including their modification with SUMO and ubiquitin chains in vitro. We discover that DPC ubiquitylation strongly activates SPRTN independently of SPRTN's known ubiquitin-binding domains. Using protein structure prediction, MD simulations and NMR spectroscopy we reveal that ubiquitin binds to SPRTN's protease domain, promoting an open, active conformation. Replacing key interfacial residues prevents allosteric activation of SPRTN by ubiquitin, leading to genomic instability and cell cycle defects in cells expressing truncated SPRTN variants that cause premature aging and liver cancer in Ruijs-Aalfs syndrome patients. Collectively, our results reveal a ubiquitin-dependent regulatory mechanism that ensures SPRTN activity is deployed precisely when and where it is needed.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna-damage; Cross-link; Dvc1 C1orf124; Parameters; Cleavage; Spartan; Repair; Pk
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 5422 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Grants Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU) - Deutsche Forschungsgemeinschaft
European Research Council
Deutsche Forschungsgemeinschaft
Vallee Foundation Scholarship
Alfried-Krupp von Bohlen und Halbach-Stiftung
ERC
International Max-Planck Research School for Molecules of Life - European Research Council