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PXD011356

PXD011356 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleIdentification of novel pyrazolopyrimidine compounds that modulate the shelterin complex and telomere length regulation via phosphoglycerate kinase 1 and stress sensor DJ1
DescriptionTelomere 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.
HostingRepositoryPRIDE
AnnounceDate2019-07-19
AnnouncementXMLSubmission_2019-08-13_04:45:17.xml
DigitalObjectIdentifierhttp://dx.doi.org/10.6019/PXD011356
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterDavid Sumpton
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListPhospho; Oxidation; Acetyl; Carbamidomethyl
InstrumentLTQ Orbitrap Velos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-10-15 03:56:52ID requested
12019-07-19 06:59:40announced
22019-08-13 03:30:25announcedUpdated publication reference for PubMed record(s): 31401411.
32019-08-13 04:45:18announcedUpdated publication reference for PubMed record(s): 31401411.
Publication List
Bilsland AE, Liu Y, Turnbull A, Sumpton D, Stevenson K, Cairney CJ, Boyd SM, Roffey J, Jenkinson D, Keith WN, A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation. Neoplasia, 21(9):893-907(2019) [pubmed]
Keyword List
curator keyword: Biological
submitter keyword: telomere, shelterin, TRF2, PGK1, DJ1, stress
Contact List
Nicol Keith
contact affiliationInstitute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK
contact emailnicol.keith@glasgow.ac.uk
lab head
David Sumpton
contact affiliationBICR
contact emaild.sumpton@beatson.gla.ac.uk
dataset submitter
Full Dataset Link List
Dataset FTP location
PRIDE project URI
Repository Record List
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