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First published online November 9, 2005
doi: 10.1242/10.1242/jcs.02718

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Secrets of a double agent: CDK7 in cell-cycle control and transcription

Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

View larger version (13K): [in a new window]   Fig. 1. The ordering of the two universal steps in CDK activation is variable. In pathway 1, binding of cyclin to form an inactive complex precedes phosphorylation within the activation loop by a CAK. This is the obligate pathway for activation of CDK1–cyclin-B complexes by CDK7 in metazoan cells (Fisher and Morgan, 1994; Desai et al., 1995). The steps are switched around in pathway 2, in which a CAK phosphorylates the T-loop of a monomeric CDK, which only becomes active upon subsequent binding of a cyclin. This is the preferred, but not obligate, pathway for activation of CDKs by the fungal CAKs: Cak1 (Ross et al., 2000) and Csk1 (Tsakraklides and Solomon, 2002). It is also a pathway available to metazoan CDK2, which can be efficiently phosphorylated by CDK7 in the absence of a cyclin partner (Fisher and Morgan, 1994; S. Larochelle and R.P.F., unpublished).

View larger version (19K): [in a new window]   Fig. 2. Alternative strategies to link CDK activation to RNA polymerase II (Pol II) phosphorylation. (A) The TFIIH-associated CDK-cyclin-RING protein complex has been conserved throughout eukaryotic evolution but is incapable of activating cell-cycle CDKs in budding yeast. The monomeric kinase responsible for all known CDK-activating phosphorylation in S. cerevisiae (Cak1) has a non-essential ortholog (Csk1) with similar functions in S. pombe, but there is no such enzyme in metazoan cells. Thus, the CAK-CDK networks controlling cell division and gene expression are connected at different levels depending on the organism: directly by a common enzyme that is both a CAK and a CTD kinase in most eukaryotes, and by the upstream CAK common to both transcriptional and cell-cycle CDKs in budding yeast. Fission yeast has both connections. (B) The XPD helicase tethers, and may actively recruit, the CDK7 complex to the TFIIH core. XPD has also been proposed to sequester CAK in the cytoplasm during interphase in Drosophila embryos; its degradation by an unknown mechanism might release CDK7 to sustain the high levels of CDK activation needed during mitosis.