Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Jason M. Spaeth
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA
Salla Keskitalo
Institute of Biotechnology, University of Helsinki, Viikinkaari 1, P.O. Box 65, Helsinki FIN-00014, Finland
Min Ju Park
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA
Teemu Kivioja
Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Alison D. Clark
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA
Netta Mäkinen
Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Fangjian Gao
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA
Kimmo Palin
Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Helka Nurkkala
Institute of Biotechnology, University of Helsinki, Viikinkaari 1, P.O. Box 65, Helsinki FIN-00014, Finland
Anna Vähärautio
Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Mervi Aavikko
Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Kati Kämpjärvi
Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Pia Vahteristo
Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Chongwoo A. Kim
Department of Biochemistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Lauri A. Aaltonen
Genome-Scale Biology Program and Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Markku Varjosalo
Institute of Biotechnology, University of Helsinki, Viikinkaari 1, P.O. Box 65, Helsinki FIN-00014, Finland
Jussi Taipale
Genome-Scale Biology Program and Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum, P.O. Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland
Thomas G. Boyer
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 8257, STRF, San Antonio, TX 78229-3900, USA
Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at very high frequency (∼70%) in uterine leiomyomas. However, the influence of these mutations on Mediator function and the molecular basis for their tumorigenic potential remain unknown. To clarify the impact of these mutations, we used affinity-purification mass spectrometry to establish the global protein-protein interaction profiles for both wild-type and mutant MED12. We found that uterine leiomyoma-linked mutations in MED12 led to a highly specific decrease in its association with Cyclin C-CDK8/CDK19 and loss of Mediator-associated CDK activity. Mechanistically, this occurs through disruption of a MED12-Cyclin C binding interface that we also show is required for MED12-mediated stimulation of Cyclin C-dependent CDK8 kinase activity. These findings indicate that uterine leiomyoma-linked mutations in MED12 uncouple Cyclin C-CDK8/19 from core Mediator and further identify the MED12/Cyclin C interface as a prospective therapeutic target in CDK8-driven cancers.
