Automethylation of CARM1 allows coupling of transcription and mRNA splicing

McArdle Laboratory for Cancer Research and Human Proteomics Program, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
Nucleic Acids Research (Impact Factor: 9.11). 12/2010; 39(7):2717-26. DOI: 10.1093/nar/gkq1246
Source: PubMed


Coactivator-associated arginine methyltransferase 1 (CARM1), the histone arginine methyltransferase and coactivator for many transcription factors, is subject to multiple post-translational modifications (PTMs). To unbiasedly investigate novel CARM1 PTMs we employed high-resolution top-down mass spectrometry. Surprisingly, mouse CARM1 expressed in insect and mammalian expression systems was completely dimethylated at a single site in the C-terminal domain (CTD). We demonstrate that dimethylation of CARM1 occurs both in vivo and in vitro and proceeds via an automethylation mechanism. To probe function of automethylation, we mutated arginine 551 to lysine to create an automethylation-deficient CARM1. Although mutation of CARM1's automethylation site did not affect its enzymatic activity, it did impair both CARM1-activated transcription and pre-mRNA splicing. These results strongly imply that automethylation of CARM1 provides a direct link to couple transcription and pre-mRNA splicing in a manner differing from the other steroid receptor coactivators. Furthermore, our study identifies a self-regulatory signaling mechanism from CARM1's catalytic domain to its CTD.

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Article: Automethylation of CARM1 allows coupling of transcription and mRNA splicing

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    • "PRMT6 requires homodimerization to transfer a methyl group from SAM to the protein substrate and this could favour automethylation [27]. As documented for CARM1 (PRMT4), another member of the PRMT family, we have hypothesized that automethylation could modulate PRMT6 function [28]. Mutagenesis of the automethylation site of CARMI did not affect its catalytic activity but impaired its transcriptional and RNA-processing capacity. "
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    • "Recently, a third phosphorylation site was identified at S448, which mediates the direct interaction of CARM1 with unliganded ERα to mediate ligand-independent activation of ERα (16). Finally, using top-down mass spectrometry, we mapped a single CARM1 automethylation site to R551 (in exon 15) in recombinant mouse protein, which is conserved among all vertebrate CARM1 proteins (17). Mutation of the automethylation site from arginine to lysine does not alter the enzymatic activity of CARM1. "
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    Nucleic Acids Research 05/2013; 41(14). DOI:10.1093/nar/gkt415 · 9.11 Impact Factor
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    • "Proteins involved in pre-mRNA splicing are also modified by methylation. The coactivator-associated arginine methyltransferase 1 (CARM1), which methylates H3 at R17 and is a transcriptional coactivator, methylates RNA binding proteins ELAV1/HuR, SNRPB/SmB, SNRPC/U1C and SF3B4/SAP49 (Kuhn et al., 2011). CARM1 has a role in alternative splicing. "
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