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Vol. 16, Issue 6, 2734-2745, June 2005

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Impairment of the TFIIH-associated CDK-activating Kinase Selectively Affects Cell Cycle-regulated Gene Expression in Fission Yeast

Karen M. Lee ^*  , Ida Miklos  ^|| ¶, Hongyan Du ^* ¶, Stephen Watt , Zsolt Szilagyi ^||, Julia E. Saiz ^*, Ram Madabhushi ^* , Christopher J. Penkett , Matthias Sipiczki ^||, Jürg Bähler , and Robert P. Fisher ^*

^* Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; Programs in Biochemistry and Cell and Molecular Biology, Cornell University Graduate School of Medical Sciences, New York, NY 10021; The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; and ^|| Department of Genetics, University of Debrecen, Debrecen, Hungary

Submitted November 10, 2004; Revised March 31, 2005; Accepted April 1, 2005
Monitoring Editor: Tim Stearns

The fission yeast Mcs6–Mcs2–Pmh1 complex, homologous to metazoan Cdk7–cyclin H-Mat1, has dual functions in cell division and transcription: as a partially redundant cyclin-dependent kinase (CDK)-activating kinase (CAK) that phosphorylates the major cell cycle CDK, Cdc2, on Thr-167; and as the RNA polymerase (Pol) II carboxyl-terminal domain (CTD) kinase associated with transcription factor (TF) IIH. We analyzed conditional mutants of mcs6 and pmh1, which activate Cdc2 normally but cannot complete cell division at restrictive temperature and arrest with decreased CTD phosphorylation. Transcriptional profiling by microarray hybridization revealed only modest effects on global gene expression: a one-third reduction in a severe mcs6 mutant after prolonged incubation at 36°C. In contrast, a small subset of transcripts (5%) decreased by more than twofold after Mcs6 complex function was compromised. The signature of repressed genes overlapped significantly with those of cell separation mutants sep10 and sep15. Sep10, a component of the Pol II Mediator complex, becomes essential in mcs6 or pmh1 mutant backgrounds. Moreover, transcripts dependent on the forkhead transcription factor Sep1, which are expressed coordinately during mitosis, were repressed in Mcs6 complex mutants, and Mcs6 also interacts genetically with Sep1. Thus, the Mcs6 complex, a direct activator of Cdc2, also influences the cell cycle transcriptional program, possibly through its TFIIH-associated kinase function.

Note added in proof. While our manuscript was in review, Bamps et al. (2004) also reported that disruption of pmh1 was lethal.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present address: Department of Oncological Sciences, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029.

^¶ These authors contributed equally to this work.

Address correspondence to: Robert P. Fisher (r-fisher{at}ski.mskcc.org).

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