PXD049682

PXD049682 is an original dataset announced via ProteomeXchange.

Title	TIMELESS haploinsufficiency induces a PARG-dependency that is rescued by nucleoside supplementation, thus mimicking intrinsic PARG inhibitor sensitivity of ovarian cancer cells
Description	A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of TIMELESS, a replisome accelerator. However, the nature of the oncogenic vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analyzed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork-restart ability, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential, in both a TIMELESShaploinsufficient model and intrinsically sensitive cells. Importantly nucleoside supplementation restores PARG inhibitor resistance without reverting PAR chain accumulation, indicating that sensitivity correlates with PAR chain intolerance. We show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency, and, using label-free, quantitative proteomics, we show that PKMYT1, a negative regulator of CDK1, is overexpressed in PARG inhibitor-sensitive cells. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances, in turn applying selective pressure on mitotic entry controls to maintain genome integrity.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:47:49.580.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Holda Anagho
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	adenosine diphosphoribosyl (ADP-ribosyl) modified residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-19 06:41:12	ID requested
1	2024-06-28 01:17:27	announced
⏵ 2	2024-10-22 06:47:50	announced	2024-10-22: Updated project metadata.

10.1093/NARCAN/ZCAE030;

submitter keyword: PARG inhibitor,DNA replication, ADP-ribosylation DDA, ethcd, HGSOC, replication stress, LC-MS/MS

Stephen S. Taylor
contact affiliation	Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4GJ, United Kingdom
contact email	stephen.taylor@manchester.ac.uk
lab head
Holda Anagho
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
contact email	holda.anagho@cpr.ku.dk
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/2024/06/PXD049682

PRIDE project URI

• PRIDE
  1. PXD049682
     1. Label: PRIDE project
     2. Name: TIMELESS haploinsufficiency induces a PARG-dependency that is rescued by nucleoside supplementation, thus mimicking intrinsic PARG inhibitor sensitivity of ovarian cancer cells