PXD051378-1

PXD051378 is an original dataset announced via ProteomeXchange.

Title	DNA-Protein Crosslinks Promote cGAS-STING-driven Premature Aging and Embryonic Lethality
Description	DNA-protein crosslinks (DPCs) are severe DNA lesions that disrupt replication, transcription, and genome stability. However, their role in development and aging remains poorly understood. Here, we show that impaired SPRTN function, a metalloprotease essential for DPC repair during replication and mitosis, leads to DNA damage, mitotic abnormalities, and activation of the immune system. Notably, micronuclei formed upon SPRTN deficiency frequently contain DPCs, exhibit nuclear envelope rupture, and accumulate unrepaired DNA, thereby facilitating activation of the cGAS-STING pathway. Using a Sprtn knock-in mouse model of Ruijs Aalfs progeria syndrome, we demonstrate that chronic cGas-Sting activation drives inflammation, innate immune responses, and embryonic lethality. Surviving mice display a continuum of aging phenotypes from embryogenesis into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescues embryonic viability and ameliorates progeroid features, linking DPC-induced innate immune activation to lifespan defects. Our findings uncover a previously unrecognized role for DPCs in coupling early developmental failure to premature aging.
HostingRepository	PRIDE
AnnounceDate	2025-09-30
AnnouncementXML	Submission_2025-09-29_22:40:03.260.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thorsten Mosler
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Ascend; Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-11 18:05:00	ID requested
⏵ 1	2025-09-29 22:40:03	announced

Dataset with its publication pending

submitter keyword: innate immunity, pyroptosis., cGAS-STING, mitosis, interferon,DPCs, SPRTN, embryonic lethality

Ivan Dikic
contact affiliation	Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt; Frankfurt, Germany.
contact email	dikic@biochem2.uni-frankfurt.de
lab head
Thorsten Mosler
contact affiliation	Goethe University Clinics Frankfurt
contact email	thorstenmosler@googlemail.com
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/2025/09/PXD051378

PRIDE project URI

• PRIDE
  1. PXD051378
     1. Label: PRIDE project
     2. Name: DNA-Protein Crosslinks Promote cGAS-STING-driven Premature Aging and Embryonic Lethality