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Targeting PRMT1-mediated SRSF1 Methylation to Suppress Exon Inclusion within Oncogenic Transcripts and Breast Tumorigenesis

ABSTRACT: Targeting PRMT1-mediated SRSF1 Methylation to Suppress Exon Inclusion within Oncogenic Transcripts and Breast Tumorigenesis

PROVIDER: PRJNA873704 | ENA |

REPOSITORIES: ENA

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Targeting PRMT1-mediated SRSF1 Methylation to Suppress Exon Inclusion within Oncogenic Transcripts and Breast Tumorigenesis

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.

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Toxoplasma gondii arginine methyltransferase 1 (PRMT1) regulates parasite counting during tachyzoite cell division

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