PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion
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PROVIDER: PRJNA1228975 | ENA |
REPOSITORIES: ENA
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Project description:Protein Arginine Methyltransferase 5 (PRMT5) is a key regulator of gene expression and RNA splicing, with its therapeutic potential demonstrated through synthetic lethality in MTAP-deleted cancers. Emerging evidence also suggests that MYC-driven or p53 wild-type tumors may be more sensitive to PRMT5 inhibition, though the underlying mechanisms remain unclear. Virus-positive Merkel cell carcinoma (MCC) serves as an ideal model to explore this question, as it is driven by the MYC paralog MYCL, and most virus-positive MCCs retain wild-type p53. In this study, we investigated PRMT5’s impact on the Tip60-EP400 complex, given MCC’s reliance on the interaction between MYCL and this complex. We used second-generation sequencing (Illumina) to characterize PRMT5-mediated bulk gene expression and long-read RNA sequencing (PacBio Iso-Seq) to analyze PRMT5-mediated alternative splicing. The mechanism underlying PRMT5 deficiency's selective impact on specific splice sites while leaving others unaffected remains unclear. Our findings suggest that PRMT5-mediated methylation of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper splicing of Tip60 and maintaining Tip60-EP400 activity. In contrast, PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including both exon skipping and intron retention. These results provide new insights into PRMT5’s role in splicing regulation in cancer cells and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.
2025-08-20 | GSE290105 | GEO
Project description:Protein Arginine Methyltransferase 5 (PRMT5) is a key regulator of gene expression and RNA splicing, with its therapeutic potential demonstrated through synthetic lethality in MTAP-deleted cancers. Emerging evidence also suggests that MYC-driven or p53 wild-type tumors may be more sensitive to PRMT5 inhibition, though the underlying mechanisms remain unclear. Virus-positive Merkel cell carcinoma (MCC) serves as an ideal model to explore this question, as it is driven by the MYC paralog MYCL, and most virus-positive MCCs retain wild-type p53. In this study, we investigated PRMT5’s impact on the Tip60-EP400 complex, given MCC’s reliance on the interaction between MYCL and this complex. We used second-generation sequencing (Illumina) to characterize PRMT5-mediated bulk gene expression and long-read RNA sequencing (PacBio Iso-Seq) to analyze PRMT5-mediated alternative splicing. The mechanism underlying PRMT5 deficiency's selective impact on specific splice sites while leaving others unaffected remains unclear. Our findings suggest that PRMT5-mediated methylation of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper splicing of Tip60 and maintaining Tip60-EP400 activity. In contrast, PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including both exon skipping and intron retention. These results provide new insights into PRMT5’s role in splicing regulation in cancer cells and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.
2025-08-20 | GSE290569 | GEO
Project description:PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion [JNJvsDMSO_raw]
| PRJNA1226215 | ENA
Project description:PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion [PacBio Sequel IIe]
| PRJNA1228633 | ENA
Project description:PRMT1 is highly expressed in breast tumors, and has been suggested to play a vital role in breast tumorigenesis, but the underlying molecular mechanisms remain to be fully characterized. Here, we reveal that PRMT1 exhibits a wide-spreading role in RNA alternative splicing based on transcriptome analysis, with a preference for exon inclusion in a large cohort of oncogenic genes. Profiling PRMT1 methylome reveals that the arginine/serine-rich splicing factor SRSF1 is heavily arginine-methylated by PRMT1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and PRMT1-induced exon inclusion. In breast tumors, the overexpression of PRMT1 is associated with high levels of SRSF1 arginine methylation and aberrant exon inclusion in those oncogenic genes. Accordingly, PRMT1-mediated SRSF1 methylation and exon inclusion events are found to be critical for the malignant behaviors of breast cancer cells. Furthermore, we identified and characterized a selective PRMT1 inhibitor iPRMT1, which is potent in inhibiting PRMT1-mediated SRSF1 methylation and exon inclusion events, and breast cancer cell growth both in vitro and in vivo. Combination treatment with iPRMT1 and inhibitor targeting SRSF1 phosphorylation, SPHINX31 or SRPIN340, exhibits synergistic effects on suppressing breast cancer cell growth, strengthening the cross-talk between arginine methylation and phosphorylation in SRSF1. In conclusion, our data uncover a key mechanism underlying PRMT1-mediated gene alternative splicing, demonstrating targeting PRMT1 has great potential to treat breast cancer in clinic.
2023-10-02 | GSE212049 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-08-20 | GSE290609 | GEO
Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.
2019-08-21 | PXD014792 | Pride
Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.
2019-11-08 | PXD013611 | Pride
Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for a range of malignancies. In this study, we aimed to further elucidate the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using multiplexed quantitative proteomics, we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This analysis revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 regulates binding of SRSF1 to mRNAs and proteins in leukemia and provide potential biomarkers for the treatment response to PRMT5 inhibitors.
2019-08-20 | GSE129652 | GEO
Project description:Merkel cell carcinoma is supposed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCV) and other poorly known events. A transcriptional profiling with cDNA microarrays was performed on cells from MCV+ Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and down-regulated genes. The extensive list of genes identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy. Two-conditions experiment, MCV vs Normal Merkel Cell. Biological replicates : 4 MCV (Cy5), 1 control = pool of Normal Merkel cells from 3 liftings
2014-01-01 | E-GEOD-50434 | biostudies-arrayexpress