The Arginine Methyltransferase CARM1 Regulates the Coupling of Transcription and mRNA Processing

• Published in: Molecular cell Vol. 25; no. 1; pp. 71 - 83
• Main Authors: Cheng, Donghang, Côté, Jocelyn, Shaaban, Salam, Bedford, Mark T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2007
• Subjects: Alternative Splicing - genetics; Amino Acid Motifs; Animals; Antibodies - immunology; DNA; Exons - genetics; Histones - immunology; Humans; Methylation; Mice; Nuclear Proteins - metabolism; Protein Binding; Protein Methyltransferases - metabolism; Protein Structure, Tertiary; Protein-Arginine N-Methyltransferases - chemistry; Protein-Arginine N-Methyltransferases - deficiency; Protein-Arginine N-Methyltransferases - metabolism; RNA; RNA Processing, Post-Transcriptional; RNA, Messenger - metabolism; Substrate Specificity; Transcription Factors - metabolism; Transcription, Genetic; RNA; DNA
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2006.11.019

The coactivator-associated arginine methyltransferase CARM1 is recruited by many different transcription factors as a positive regulator. To understand the mechanism by which CARM1 functions, we sought to isolate its substrates. We developed a small-pool screening approach for this purpose and identified CA150, SAP49, SmB, and U1C as splicing factors that are specifically methylated by CARM1. We further showed that CA150, a molecule that links transcription to splicing, interacts with the Tudor domain of the spinal muscular atrophy protein SMN in a CARM1-dependent fashion. Experiments with an exogenous splicing reporter and the endogenous CD44 gene revealed that CARM1 promotes exon skipping in an enzyme-dependent manner. The identification of splicing factors that are methylated by CARM1, and protein-protein interactions that are regulated by CARM1, strongly implicates this enzyme in the regulation of alternative splicing and points toward its involvement in spinal muscular atrophy pathogenesis.