The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing.
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.
Cheng
Donghang
D
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957, USA.
Côté
Jocelyn
J
Shaaban
Salam
S
Bedford
Mark T
MT
D017398:Alternative Splicing / Q000235:genetics; D020816:Amino Acid Motifs; D000818:Animals; D000906:Antibodies / Q000276:immunology; D005091:Exons / Q000235:genetics; D006657:Histones / Q000276:immunology; D006801:Humans; D008745:Methylation; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000906:Antibodies; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D011496:Protein Methyltransferases; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1