PXD011356 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Identification of novel pyrazolopyrimidine compounds that modulate the shelterin complex and telomere length regulation via phosphoglycerate kinase 1 and stress sensor DJ1 |
Description | Telomere signalling and metabolic dysfunction are hallmarks of cell aging, and are associated with a variety of pathologies. Identification of new agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. Here we report identification and characterization of a pyrazolopyrimidine compound series that emerged from screens focused on cell immortality pathways and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We initially performed structure-activity studies on the series to develop an analogue suitable for use as a photoaffinity probe to deconvolute the cellular targets. Biophysical and structural analyses confirmed these targets, pointing to the possibility that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress have previously been linked to telomere signalling and exemplar compound CRT0063465 was found to block hypoglycaemic telomere shortening. Intriguingly, we find that both PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment not only modulates these interactions but also affects composition of the Shelterin complex, in addition to conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results highlight the power of chemical approaches in discovery of novel biological mechanisms and demonstrate therapeutic potential of the compound series. |
HostingRepository | PRIDE |
AnnounceDate | 2019-07-19 |
AnnouncementXML | Submission_2019-07-19_06:59:39.xml |
DigitalObjectIdentifier | https://dx.doi.org/10.6019/PXD011356 |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Supported dataset by repository |
PrimarySubmitter | David Sumpton |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | Phospho; Oxidation; Acetyl; Carbamidomethyl |
Instrument | LTQ Orbitrap Velos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2018-10-15 03:56:52 | ID requested | |
⏵ 1 | 2019-07-19 06:59:40 | announced | |
2 | 2019-08-13 03:30:25 | announced | Updated publication reference for PubMed record(s): 31401411. |
3 | 2019-08-13 04:45:18 | announced | Updated publication reference for PubMed record(s): 31401411. |
Publication List
Dataset with its publication pending |
Keyword List
curator keyword: Biological |
submitter keyword: telomere, shelterin, TRF2, PGK1, DJ1, stress |
Contact List
Nicol Keith |
contact affiliation | Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK |
contact email | nicol.keith@glasgow.ac.uk |
lab head | |
David Sumpton |
contact affiliation | BICR |
contact email | d.sumpton@beatson.gla.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD011356
- Label: PRIDE project
- Name: Identification of novel pyrazolopyrimidine compounds that modulate the shelterin complex and telomere length regulation via phosphoglycerate kinase 1 and stress sensor DJ1