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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_H3B-8800 24h]

ABSTRACT: Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_H3B-8800 24h]

PROVIDER: PRJNA580500 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10368238_1.fastq.gz	Fastqsanger.gz
	SRR10368238_2.fastq.gz	Fastqsanger.gz
	SRR10368239_1.fastq.gz	Fastqsanger.gz
	SRR10368239_2.fastq.gz	Fastqsanger.gz
	SRR10368240_1.fastq.gz	Fastqsanger.gz

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_H3B-8800]

Project description:Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_H3B-8800]

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_H3B-8800 6hr]

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia

Project 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.

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_H3B-8800 24h]

Project description:In this study, we show that pediatric T-cell acute lymphoblastic leukemia (T-ALL) has an alternative mechanism for aberrant splicing that involves post-translational regulation of the splicing machinery via deubiquitination.

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Cotranscriptional exon skipping in the genotoxic stress response

Project description:Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin, inhibit the interaction between EWS, an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene encoding the main p53 ubiquitin-ligase. This reversible exon skipping participates in the timely regulation of MDM2 expression, and may contribute to the accumulation of p53 during stress exposure and its rapid shut off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to camptothecin and EWS/YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, resulting in widespread exon skipping and playing a central role in the genotoxic stress response. 6 samples of MCF7 cells exposed to different treatments were analyzed: 3 x control_6 hours; 3 x camptothecin_6 hours.

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia

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Targeted exon skipping with AAV-mediated split adenine base editors.

Project description:Techniques for exclusion of exons from mature transcripts have been applied as gene therapies for treating many different diseases. Since exon skipping has been traditionally accomplished using technologies that have a transient effect, it is particularly important to develop new techniques that enable permanent exon skipping. We have recently demonstrated that this can be accomplished using cytidine base editors for permanently disabling the splice acceptor of target exons. We now demonstrate the application of adenine-deaminase base editors to disrupt the conserved adenosine within splice acceptor sites for programmable exon skipping. We also demonstrate that by altering the amino acid sequence of the linker between the adenosine deaminase domain and the Cas9 nickase or by coupling the adenine base editor with a uracil glycosylase inhibitor, the DNA editing efficiency and exon skipping rates improve significantly. Finally, we developed a split base editor architecture compatible with adeno-associated viral packaging. Collectively, these results represent significant progress towards permanent in vivo exon skipping through base editing and, ultimately, a new modality of gene therapy for the treatment of genetic diseases.

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Project description:Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_P5091]

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Project description:Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_P5091]

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