PXD032188 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Signalling Inhibition by Ponatinib Disrupts Productive Alternative Lengthening of Telomeres (ALT) |
Description | Alternative lengthening of telomeres (ALT) supports telomere maintenance and replicative immortality in around 10-15% of cancers, thus representing a compelling target for therapy.To identify anti-cancer drugs that can be repurposed as ALT-centered therapies, we performed for a compound library screen on isogenic cell lines that rely either on telomerase or ALT mechanisms. We validated candidates on a panel of ALT- vs. telomerase-positive sarcoma cells and assessed levels of extrachromosomal telomeric C-circles after drug treatment, as a bona fide marker of ALT activity. We identified a receptor tyrosine kinase inhibitor ponatinib that deregulated ALT mechanisms, increased telomeric replicative stress and induced telomeric dysfunction in ALT cells. Using a model of ALT sarcoma xenografts, we found that ponatinib targeted ALT-positive cells and mitigated telomere elongation in these tumors. To identify the mode of action of ponatinib on ALT, we performed RNA-sequencing and quantitative proteomic and phosphoproteomic analyses, and shortlisted candidates to test the effect of their loss on telomeric C-circle levels. We identified an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing extrachromosomal telomeric C-circle formation. Furthermore, transcriptome and interactome analyses of JUN suggested a role of JUN in DNA damage repair pathways, independently of its capacity as a transcription factor. These results were corroborated by new synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors such as triciribine and KU-60019, respectively. Overall, we identified a novel signalling pathway impacting ALT which can be targeted by a clinically approved kinase inhibitor. |
HostingRepository | PRIDE |
AnnounceDate | 2022-03-14 |
AnnouncementXML | Submission_2022-03-14_04:49:37.836.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Dennis Kappei |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-03-10 14:31:25 | ID requested | |
⏵ 1 | 2022-03-14 04:49:38 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Ponatinib, ALT, telomeres, singalling, phosphoproteomics, sarcoma |
Contact List
Dennis Kappei |
contact affiliation | Cancer Science Institute of Singapore, National University of Singapore |
contact email | dennis.kappei@nus.edu.sg |
lab head | |
Dennis Kappei |
contact affiliation | Cancer Science Institute of Singapore |
contact email | dennis.kappei@nus.edu.sg |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD032188
- Label: PRIDE project
- Name: Signalling Inhibition by Ponatinib Disrupts Productive Alternative Lengthening of Telomeres (ALT)