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Molecular and Cellular Biology, April 2006, p. 2736-2745, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2736-2745.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of the CDK12/Cyclin L1 Complex Involved in Alternative Splicing Regulation{dagger}

Hung-Hsi Chen,1 Yu-Chiuan Wang,1 and Ming-Ji Fann1,2,3*

Institute of Neuroscience,1 Faculty of Life Sciences, National Yang-Ming University,2 Brain Research Center, University System of Taiwan, Taipei 11221, Taiwan, Republic of China3

Received 19 September 2005/ Returned for modification 2 November 2005/ Accepted 4 January 2006

CrkRS is a Cdc2-related protein kinase that contains an arginine- and serine-rich (SR) domain, a characteristic of the SR protein family of splicing factors, and is proposed to be involved in RNA processing. However, whether it acts together with a cyclin and at which steps it may function to regulate RNA processing are not clear. Here, we report that CrkRS interacts with cyclin L1 and cyclin L2, and thus rename it as the long form of cyclin-dependent kinase 12 (CDK12L). A shorter isoform of CDK12, CDK12S, that differs from CDK12L only at the carboxyl end, was also identified. Both isoforms associate with cyclin L1 through interactions mediated by the kinase domain and the cyclin domain, suggesting a bona fide CDK/cyclin partnership. Furthermore, CDK12 isoforms alter the splicing pattern of an E1a minigene, and the effect is potentiated by the cyclin domain of cyclin L1. When expression of CDK12 isoforms is perturbed by small interfering RNAs, a reversal of the splicing choices is observed. The activity of CDK12 on splicing is counteracted by SF2/ASF and SC35, but not by SRp40, SRp55, and SRp75. Together, our findings indicate that CDK12 and cyclin L1/L2 are cyclin-dependent kinase and cyclin partners and regulate alternative splicing.

* Corresponding author. Mailing address: Faculty of Life Sciences, National Yang-Ming University, Taipei, Taiwan 11221. Phone: 886-2-2826-7184. Fax: 886-2-2820-0259. E-mail: mjfann{at}ym.edu.tw.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2006, p. 2736-2745, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2736-2745.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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