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PTBP1 Regulates DNMT3B Alternative Splicing by Interacting with RALY to Enhance the Radioresistance of Prostate Cancer

ABSTRACT: PTBP1 Regulates DNMT3B Alternative Splicing by Interacting with RALY to Enhance the Radioresistance of Prostate Cancer

PROVIDER: PRJNA1159875 | ENA |

REPOSITORIES: ENA

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PTBP1 Regulates DNMT3B Alternative Splicing by Interacting with RALY to Enhance the Radioresistance of Prostate Cancer

Project description:Radiotherapy is a curative arsenal for prostate cancer (PCa), but radioresistance seriously compromises its effectiveness. Dysregulated RNA splicing factors are extensively involved in tumor progression. Nonetheless, the role of splicing factors in radioresistance remains largely unexplored in PCa. Here, we identified 23 splicing factors that are differentially expressed between PCa and adjacent normal tissues across multiple public PCa databases. Among those genes, polypyrimidine tract binding protein 1 (PTBP1) was significantly upregulated in PCa and was positively associated with advanced clinicopathological features and poor prognosis. Gain- and loss-of-function experiments demonstrated that PTBP1 markedly reinforced genomic DNA stability to desensitize PCa cells to irradiation in vitro and in vivo. Mechanistically, PTBP1 interacted with the HnRNP associated with lethal yellow protein homolog (RALY) and regulated exon 5 splicing of methyltransferase 3b (DNMT3B) from DNMT3B-S to DNMT3B-L. Furthermore, upregulation of DNMT3B-L induced promoter methylation of dual-specificity phosphatase-2 (DUSP2) and subsequently inhibited DUSP2 expression, thereby increasing radioresistance in PCa. Our findings highlight the role of splicing factors in inducing aberrant splicing events in response to radiotherapy and the potential role of PTBP1 and DNMT3B-L in reversing radioresistance in PCa.

2025-01-01 | GSE276977 | GEO

Regulation of co-transcriptional splicing by RNA-binding protein PTBP1

Project description:We examined the role of PTBP1 in regulation of co-transcriptional splicing process by depleting this RNA-binding protein from embryonic stem cells using the auxin-inducible degron technology and analysing the total and chromatin-associated RNA fractions by RNA-seq. We also performed mNET-seq and ChIP-seq analyses using RNA polymerase II- and PTBP1-specific antibodies, respectively. Our data suggest that PTBP1 activates co-transcriptional splicing of hundreds of introns, a surprising effect given that PTBP1 is better known as a splicing repressor. Importantly, some co-transcriptionally activated introns fail to be spliced post-transcriptionally without PTBP1. In a striking example of this regulation, lasting retention of a PTBP1-dependent intron triggers nonsense-mediated decay of mRNAs encoding DNA methyltransferase DNMT3B, explaining their natural expression dynamics in development. Our further analyses suggest that this mechanism may protect differentiation-specific genes from aberrant methylation. We conclude that PTBP1-activated co-transcriptional splicing underlies biologically important decisions.

2023-01-08 | E-MTAB-11544 | biostudies-arrayexpress

Hsa_circ_0005358 suppresses cervical cancer metastasis via interacting with PTBP1 protein to destabilize CDCP1 mRNA [si-oligo vs si-PTBP1]

Project description:Hsa_circ_0005358 suppresses cervical cancer metastasis via interacting with PTBP1 protein to destabilize CDCP1 mRNA [si-oligo vs si-PTBP1]

| PRJNA714554 | ENA

Hsa_circ_0005358 suppresses cervical cancer metastasis via interacting with PTBP1 protein to destabilize CDCP1 mRNA [si-oligo vs si-PTBP1]

Project description:Function exploration of hsa_circ_0005358 in cervical cancer cells ;Mechanism of how hsa_circ_0005358 works via its protein partner PTBP1.

2022-06-14 | GSE168907 | GEO

iiCLIP protocol benchmarking with PTBP1

Project description:We describe an improved individual nucleotide resolution CLIP protocol (iiCLIP), which can be completed within 4 days from UV crosslinking to libraries for sequencing. For benchmarking, we directly compared PTBP1 iiCLIP libraries with the iCLIP2 protocol produced under standardised conditions with 1 million HEK293 cells, and with public eCLIP and iCLIP PTBP1 data. There are 3 PTBP1 iiCLIP libraries, 1 input iiCLIP library and 1 PTBP1 iCLIP2 library produced in this study.

2022-08-01 | E-MTAB-10881 | biostudies-arrayexpress

Proteome changes in PTBP1 deficient hematopoietic cells

Project description:Ribosomopathies constitute a range of disabling conditions associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here we demonstrate that deletion of Polypyrimidine Tract Binding Protein 1 (PTBP1) in the hematopoietic compartment led to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 was associated with a decrease in HSC self-renewal, erythroid differentiation and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency led to splicing defects in hundreds of genes and we demonstrate that the up-regulation of a specific isoform of CDC42 could partly mimic the protein synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency was associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA binding proteins.

2022-05-04 | PXD023879 | Pride

Hsa_circ_0005358 suppresses cervical cancer metastasis via interacting with PTBP1 protein to destabilize CDCP1 mRNA

Project description:Hsa_circ_0005358 suppresses cervical cancer metastasis via interacting with PTBP1 protein to destabilize CDCP1 mRNA

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Polypyrimidine Tract Binding Proteins PTBP1 and PTBP2 Interact with Distinct Proteins Under Splicing Conditions

Project description:RNA binding proteins play an important role in regulating alternative pre-mRNA splicing and in turn cellular gene expression. Polypyrimidine tract binding proteins, PTBP1 and PTBP2, are paralogous RNA binding proteins that play a critical role in the process of neuronal differentiation and maturation; changes in the concentration of PTBP proteins during neuronal development direct splicing changes in many transcripts that code for proteins critical for neuronal differentiation. How the two related proteins regulate different sets of neuronal exons is unclear. The distinct splicing activities of PTBP1 and PTBP2 can be recapitulated in an in vitro splicing system with the differentially regulated N1 exon of the c-src pre-mRNA. Here, we conducted experiments under these in vitro splicing conditions to identify PTBP1 and PTBP2 interacting partner proteins.

2022-01-20 | PXD029899 | Pride

Hsa_circ_0005358 suppresses cervical cancer metastasis via interacting with PTBP1 protein to destabilize CDCP1 mRNA [vector vs has_circ005358 overexpression]

Project description:Functional exploration of hsa_circ_0005358 in cervical cancer cells ;Mechanism of how hsa_circ_0005358 works via its protein partner PTBP1.

2022-06-14 | GSE168549 | GEO

PTBP1 - Modified iCLIP

Project description:PTBP1 - Modified iCLIP

| PRJEB15236 | ENA