PXD074872-1

PXD074872 is an original dataset announced via ProteomeXchange.

Title	Chemogenetic TAK-243 CRISPR Screen Uncovers HAPSTR1/HUWE1 Axis in Chromatin Proteostasis and Cell Cycle Control
Description	CellProteostasis and cell cycle progression is orchestrated by a complex interplay between post-translational modifications (PTMs) thatare both subject to ubiquitin-mediated control activation (phosphorylation) and degradation (ubiquitination) of key cell cycle regulators. To. Here, we sought to comprehensively identifymap ubiquitin signalling components critical for cellcellular proliferation, we employed through a chemical-genetic CRISPR knock-out screen exploiting the first-in-class ubiquitin E1 inhibitor TAK-243. Our findings provide a systems view ofWe identified key protein networks underpinning cell cycle progression. Overall, we identified, with 239 genes, including C16orf72/HAPSTR1 and its interacting E3 ubiquitin ligase HUWE1, whose ablation renderssensitizes cells sensitive to ubiquitin signalling blockade, andas well as 55 genes that conferwhose loss confers resistance under the same conditions. Mechanistically, we revealfind that HAPSTR1 regulates proteostasis at the chromatin through recruitment of HUWE1, and in so doing promotes proper DNA replication fidelity and cell cycle progression. In turn, HUWE1 induces cell cycle-dependent turnover of HAPSTR1. Loss of HAPSTR1 expression impairs clearance of chromatin-associated proteins, triggering widespread cell cycle, transcriptional and ubiquitinome-wideproteostatic adaptations to safeguard cellular proliferation. However, under diminished ubiquitin signalling, these adaptive mechanisms fail to compensate for impaired chromatin proteostasisloss of HAPSTR1, resulting in knock-on effects of replication stress, premature S phase entry downstream of CDK6 and collapse of, ultimately, cell cycle integrity. Syntheticcollapse. Synthetic lethality of HAPSTR1 loss with ubiquitin signalling blockade results from reduced chromatin proteostasis leading to transcriptional deregulation and loss of cell cycle integrity .Our findings highlight protein networks exhibiting synthetic lethality of HAPSTR1 loss with ubiquitin signalling blockade. can be envisioned to result from compounding effects of altered proteostasis, transcriptional deregulation and cell cycle anomalies, collectively culminating inuncover the HAPSTR1/HUWE1 axis as a multifaceted cycle ofkey regulatory node at the juncture of chromatin proteostasis and cellular stressproliferation.
HostingRepository	PRIDE
AnnounceDate	2026-09-01
AnnouncementXML	Submission_2026-09-01_03:47:16.796.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported 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	2026-02-25 00:32:24	ID requested
⏵ 1	2026-09-01 03:47:17	announced
2	2026-09-01 03:55:24	announced	2026-09-01: Updated project metadata.

Dataset with its publication pending

submitter keyword: Cell cycle, S phasechromatin proteostasis, HAPSTR1, ubiquitin signalling, HUWE1

Alfred Vertegaal
contact affiliation	Department of Cell and Chemical Biology, Leiden University Medical Center, 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/PXD074872

PRIDE project URI

• PRIDE
  1. PXD074872
     1. Label: PRIDE project
     2. Name: Chemogenetic TAK-243 CRISPR Screen Uncovers HAPSTR1/HUWE1 Axis in Chromatin Proteostasis and Cell Cycle Control