PXD063921

PXD063921 is an original dataset announced via ProteomeXchange.

Title	Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability
Description	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 ubiquitin-dependent activation of SPRTN, 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 novel ubiquitin-dependent regulatory principle in DNA repair that ensures SPRTN activity is deployed precisely when and where it is needed.
HostingRepository	PRIDE
AnnounceDate	2025-07-24
AnnouncementXML	Submission_2025-07-23_21:24:36.410.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Petra Beli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitination signature dipeptidyl lysine
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-14 03:57:57	ID requested
⏵ 1	2025-07-23 21:24:36	announced

10.1038/S41467-025-61224-Z;

submitter keyword: DNA repair,DNA-Protein crosslinks (DPCs), SPRTN, Ubiquitin

Petra Beli
contact affiliation	Institute of Molecular Biology gGmbH, Mainz, Germany Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-Universität Mainz, Germany
contact email	p.beli@imb-mainz.de
lab head
Petra Beli
contact affiliation	Institute of Molecular Biology (IMB), Mainz, Germany
contact email	p.beli@imb-mainz.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/07/PXD063921

PRIDE project URI

• PRIDE
  1. PXD063921
     1. Label: PRIDE project
     2. Name: Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability