Article

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

ABSTRACT 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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    • "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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    • "Moreover, AtPRMT10 R13K could fully rescue the late-flowering defect of the atprmt10-1 mutant. Nevertheless, it is worth noting that the auto-methylation of mouse CARM1 has been shown to link transcription and pre-mRNA splicing (Kuhn et al., 2011). The biological significance of AtPRMT10 auto-methylation remains to be investigated in Arabidopsis. "
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    • "Similarly, post-translational phosphorylation at tyrosine-87 increased interaction with rpS2 and enzymatic activity of PRMT3 (Handrkova et al., 2011), whereas the same modification at serine-229 blocks dimerization and significantly decreases MTase activity of CARM1 (Feng et al., 2009). In addition, automethylation of CARM1 was also found to be essential for its in vivo functions (Kuhn et al., 2011). Lastly, truncation analysis demonstrated that N-termini of PRMT8 and AtPRMT10 negatively regulate their enzymatic activity (Sayegh et al., 2007; Cheng et al., 2011). "
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