Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth

Nat Commun. 2021 Mar 29;12(1):1946. doi: 10.1038/s41467-021-21963-1.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Arginine / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1 / antagonists & inhibitors
  • Heterogeneous Nuclear Ribonucleoprotein A1 / genetics*
  • Heterogeneous Nuclear Ribonucleoprotein A1 / metabolism
  • Humans
  • Male
  • Methylation / drug effects
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors
  • Protein-Arginine N-Methyltransferases / genetics*
  • Protein-Arginine N-Methyltransferases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Spliceosomes / drug effects
  • Spliceosomes / genetics
  • Spliceosomes / metabolism
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • RNA, Small Interfering
  • hnRNPA1 protein, human
  • Arginine
  • PRMT5 protein, human
  • PRMT7 protein, human
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1