PXD015587

PXD015587 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2019-09-25 20:21:35	ID requested
⏵ 1	2020-08-30 16:05:41	announced

no publication

submitter keyword: T-cell Leukemia, Post-translation regulation

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

MassIVE dataset URI

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