PXD051267-1

PXD051267 is an original dataset announced via ProteomeXchange.

Title	Ubiquitin E3 ligases UBR4, UBR5 and HUWE1 protect human genome integrity by targeting cancer-associated APOBEC3 deaminases for degradation
Description	Members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family play crucial roles as viral restriction factors, yet some APOBEC3 (A3) members drive harmful hypermutation in humans, contributing to cancer. These cancer-associated A3 members have reduced RNA-mediated retention in the cytosol, and therefore can drive nuclear DNA mutation. We show that specifically major cancer-associated members are rapidly turned-over by proteasomes, indicating the existence of cellular pathways marking cancer-associated A3s for degradation, thereby protecting cellular genomic DNA from hypermutation. Through genetic and proteomic screening UBR4, UBR5 and HUWE1 were identified as degraders of cancer-associated A3 proteins, thereby limiting A3-driven hypermutation. Mechanistically, UBR5 and HUWE1 recognize the unengaged RNA-binding interface of cancer-associated A3B and A3H-I, promoting their proteasomal degradation. Depletion or mutation of the E3 ligases in cell models and cancer samples increased A3-driven hypermutation. Our findings highlight UBR4, UBR5 and HUWE1 as crucial factors in maintaining human genome stability.
HostingRepository	PRIDE
AnnounceDate	2025-12-22
AnnouncementXML	Submission_2025-12-22_00:34:10.673.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Markus Hartl
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	biotinylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-08 01:58:53	ID requested
⏵ 1	2025-12-22 00:34:11	announced

Dataset with its publication pending

submitter keyword: genome integrity, RNA binding,APOBEC, cytidine deaminase, proteasome, protein degradation, ubiquitin, E3 ligase, APOBEC signature

Gijs Versteeg
contact affiliation	Max Perutz Labs, University of Vienna
contact email	gijs.versteeg@univie.ac.at
lab head
Markus Hartl
contact affiliation	Max Perutz Labs, Mass Spectrometry Facility, Vienna Biocenter Campus (VBC), Dr. Bohr-Gasse 9, Vienna, Austria
contact email	proteomics@maxperutzlabs.ac.at
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/2025/12/PXD051267

PRIDE project URI

• PRIDE
  1. PXD051267
     1. Label: PRIDE project
     2. Name: Ubiquitin E3 ligases UBR4, UBR5 and HUWE1 protect human genome integrity by targeting cancer-associated APOBEC3 deaminases for degradation