Abstract
Numerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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Amino Acid Sequence
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Arginine / metabolism
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Line, Tumor
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Enzyme Inhibitors / pharmacology
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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HEK293 Cells
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Heterogeneous Nuclear Ribonucleoprotein A1 / antagonists & inhibitors
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Heterogeneous Nuclear Ribonucleoprotein A1 / genetics*
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Heterogeneous Nuclear Ribonucleoprotein A1 / metabolism
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Humans
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Male
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Methylation / drug effects
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Binding
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Protein Processing, Post-Translational
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Protein-Arginine N-Methyltransferases / antagonists & inhibitors
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Protein-Arginine N-Methyltransferases / genetics*
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Protein-Arginine N-Methyltransferases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Spliceosomes / drug effects
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Spliceosomes / genetics
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Spliceosomes / metabolism
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Substrate Specificity
Substances
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Enzyme Inhibitors
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Heterogeneous Nuclear Ribonucleoprotein A1
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RNA, Small Interfering
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hnRNPA1 protein, human
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Arginine
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PRMT5 protein, human
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PRMT7 protein, human
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Protein-Arginine N-Methyltransferases
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coactivator-associated arginine methyltransferase 1