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J. Biol. Chem., Vol. 280, Issue 32, 28927-28935, August 12, 2005

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Coactivator-associated Arginine Methyltransferase 1, CARM1, Affects Pre-mRNA Splicing in an Isoform-specific Manner^*

Naganari Ohkura, Maho Takahashi, Hiroko Yaguchi, Yuko Nagamura, and Toshihiko Tsukada

From the Tumor Endocrinology Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan

Molecular diversity through alternative splicing is important for cellular function and development. However, little is known about the factors that regulate alternative splicing. Here we demonstrate that one isoform of coactivator-associated arginine methyltransferase 1 (named CARM1-v3) associates with the U1 small nuclear RNP-specific protein U1C and affects 5' splice site selection of the pre-mRNA splicing. CARM1-v3 was generated by the retention of introns 15 and 16 of the primary transcript of CARM1. Its deduced protein lacks the C-terminal domain of the major isoform of CARM1 and instead has v3-specific sequences at the C terminus. CARM1-v3, but not the other isoforms, strongly stimulates a shift to the distal 5' splice site of the pre-mRNA when the adenoviral E1A minigene is used as a reporter and enhances the exon skips in the CD44 reporter. A CARM1-v3 mutant lacking the v3-specific sequences completely lost the ability to regulate the alternative splicing patterns. In addition, CARM1-v3 shows tissue-specific expression patterns distinct from those of the other isoforms. These results suggest that the transcriptional coactivator can affect the splice site decision in an isoform-specific manner.

Received for publication, February 25, 2005 , and in revised form, May 27, 2005.

^* This work was supported in part by Grant-in-aid for Scientific Research 15510168 from Japan Society for the Promotion of Science (to N. O.) and by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan (to T. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB201114 (CARM1-v1), AB201115 (CARM1-v2), AB201116 (CARM1-v3), and AB201117 (CARM1-v4).

To whom correspondence should be addressed. Tel.: 81-3-3542-2511; Fax: 81-3-3542-8170; E-mail: nohkura{at}gan2.res.ncc.go.jp.

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