PXD049697

PXD049697 is an original dataset announced via ProteomeXchange.

Title	Chemogenetic Ubiquitin E1 Inhibitor TAK-243 CRISPR Screen Uncovers HAPSTR1/HUWE1 Axis in Chromatin Proteostasis and Cell Cycle Control
Description	We sought to comprehensively map ubiquitin signalling networks at the crossroads of cellular proliferation and proteostasis. Genome-wide CRISPR knock-out screening in the presence of the ubiquitin E1 inhibitor TAK-243 identified 239 genes whose ablation sensitizes cells to ubiquitination blockade. Follow-up studies reveal a role for the nuclear protein, C16orf72/HAPSTR1, in chromatin proteostasis and DNA replication. We show that HAPSTR1 recruits the E3 ligase HUWE1 to the chromatin and carry out structural modelling of the HAPSTR1/HUWE1 complex and validate the model by point mutation of HAPSTR1. HUWE1 induces turnover of HAPSTR1 during cell cycle progression. Consequently, HAPSTR1 ablation impairs clearance of chromatin-associated proteins, triggering global transcriptional and proteostatic adaptations. Under diminished ubiquitin signalling, these adaptive mechanisms give way to replication stress and premature S phase entry, culminating in cell cycle collapse and DNA damage. Our findings uncover protein networks exhibiting synthetic lethality with ubiquitin signalling blockade and highlight vulnerabilities of actively proliferating cells to proteostatic imbalance at the chromatin.
HostingRepository	PRIDE
AnnounceDate	2026-09-01
AnnouncementXML	Submission_2026-09-01_03:54:25.179.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD049697
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Nila Overbeek
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-19 11:34:35	ID requested
1	2026-09-01 03:52:53	announced
⏵ 2	2026-09-01 03:54:25	announced	2026-09-01: Updated project metadata.

10.6019/PXD049697;

submitter keyword: Ubiquitin, C16orf72, TAK243, HAPSTR1, cell cycle, HUWE1

Alfred C. O. Vertegaal
contact affiliation	Cell & Chemical Biology LUMC Leiden The Netherlands
contact email	a.c.o.vertegaal@lumc.nl
lab head
Nila Overbeek
contact affiliation	LUMC
contact email	n.k.van_overbeek@lumc.nl
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/2026/09/PXD049697

PRIDE project URI

• PRIDE
  1. PXD049697
     1. Label: PRIDE project
     2. Name: Chemogenetic Ubiquitin E1 Inhibitor TAK-243 CRISPR Screen Uncovers HAPSTR1/HUWE1 Axis in Chromatin Proteostasis and Cell Cycle Control