PXD015587-1
PXD015587 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia |
Description | Splicing alterations are very common in cancer and might affect disease initiation and progression. In several cancers, mutations in splicing factor genes are responsible for aberrant splicing. We show that certain aggressive cancers, such as pediatric T-cell acute lymphoblastic leukemia (T-ALL), have an alternative mechanism for aberrant splicing that involves post-translational regulation of the splicing machinery via deubiquitination. We initially demonstrated that T-ALL presents with extensive exon skipping events affecting proteasomal transcripts, cell cycle and epigenetic regulators. Performing an unbiased genetic screen study for RNA binding proteins, we showed that the serine/arginine-rich splicing factor (SRSF) proteins, controlling exon skipping are critical for T-ALL survival. In our effort to dissect mechanisms of aberrant regulation of SRSF proteins, we focused on the pro-oncogenic deubiquitinase ubiquitin-specific peptidase 7 (USP7) to show it regulates the levels of the SRSF proteins at the post-translational level via active deubiquitination. We further demonstrated that USP7 inhibitors can change the splicing landscape and block T-ALL growth. Our drug studies show that decrease of the levels of SRSF proteins splicing inhibitors sensitize cells to the clinically used splicing inhibitor H3B-8800. Driven by our molecular findings on aberrant splicing of proteasomal transcripts, we demonstrate that H3B-8800 could act synergistically with proteasome inhibitors, paving the way for new therapeutic schemes in pediatric leukemia. Collectively this study provides the proof-of-principle for regulation of splicing factors independently of mutations and via deubiquitination and suggests new therapeutic modalities and combinations in cancer. |
HostingRepository | MassIVE |
AnnounceDate | 2020-08-30 |
AnnouncementXML | Submission_2020-08-30_16:05:41.xml |
DigitalObjectIdentifier | |
ReviewLevel | Non peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Supported dataset by repository |
PrimarySubmitter | Cho Byoung-Kyu |
SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
ModificationList | ubiquitination signature dipeptidyl lysine |
Instrument | LTQ Orbitrap Velos; Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2019-09-25 20:21:35 | ID requested | |
⏵ 1 | 2020-08-30 16:05:41 | announced |
Publication List
no publication |
Keyword List
submitter keyword: T-cell Leukemia, Post-translation regulation |
Contact List
Young Ah Goo | |
---|---|
contact affiliation | Northwestern University |
contact email | young.goo@northwestern.edu |
lab head | |
Panagiotis Ntziachristos | |
contact affiliation | Northwestern University |
contact email | Panos.ntz@northwestern.edu |
lab head | |
Cho Byoung-Kyu | |
contact affiliation | Northwestern University |
contact email | byoungkyu.cho@northwestern.edu |
dataset submitter |
Full Dataset Link List
MassIVE dataset URI |
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://massive.ucsd.edu/MSV000084383/ |