Alternative titles; symbols
HGNC Approved Gene Symbol: CCNH
Cytogenetic location: 5q14.3 Genomic coordinates (GRCh38): 5:87,311,471-87,412,930 (from NCBI)
The cdk-activating kinase (CAK) is a multi-subunit protein which phosphorylates and thus activates certain cyclin-dependent protein kinases in the regulation of cell cycle progression. Fisher and Morgan (1994) purified mammalian CAK and found that it was composed of 2 major polypeptides, a 37-kD cyclin termed cyclin H and a 42-kD cyclin-dependent kinase (CDK7; 601955). Fisher and Morgan (1994) cloned the cyclin H gene encoding a 323-amino acid polypeptide homologous to STK1 (CDK7) and Xenopus MO15, a cell cycle-associated kinase. The authors reported that a reconstituted cyclin H/CDK7 complex was able to phosphorylate CDK2 (116953) and CDC2 (116940) in vitro.
Shiekhattar et al. (1995) purified transcription factor IIH (TFIIH; see 189972) and found that it contained material that reacted with antibodies to CDK7 and cyclin H. The authors confirmed the presence of the CAK complex as a distinct component of TFIIH, suggesting a link between TFIIH (by the phosphorylation of CDC2 or CDK2) and the processes of transcription, DNA repair, and cell cycle progression.
Mammalian CDK8 (603184) and cyclin C (123838) are components of the RNA polymerase II holoenzyme complex, where they function as a protein kinase that phosphorylates the C-terminal domain of the largest subunit of RNA polymerase II. The CDK8/cyclin C protein complex is also found in a number of mammalian 'Mediator'-like protein complexes, which repress activated transcription independently of the C-terminal domain in vitro. Akoulitchev et al. (2000) demonstrated that CDK8/cyclin C can regulate transcription by targeting the CDK7/cyclin H subunits of TFIIH. CDK8 phosphorylates mammalian cyclin H at serine-5 and serine-304 both in vitro and in vivo, in the vicinity of its functionally unique N- and C-terminal alpha-helical domains. This phosphorylation represses both the ability of TFIIH to activate transcription and its C-terminal kinase activity. In addition, mimicking CDK8 phosphorylation of cyclin H in vivo has a dominant-negative effect on cell growth. Akoulitchev et al. (2000) concluded that their results linked the Mediator complex and the basal transcription machinery by a regulatory pathway involving 2 cyclin-dependent kinases. This pathway appears to be unique to higher organisms.
Andersen et al. (1996) found the crystal structure of cyclin H to be similar to the structure of cyclin A (123835), both containing the canonical cyclin fold.
Eki et al. (1998) used somatic cell hybrid panels, fluorescence in situ hybridization, and YAC contigs to map the cyclin H gene to human chromosome 5q13.3-q14.
Akoulitchev, S., Chuikov, S., Reinberg, D. TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407: 102-106, 2000. [PubMed: 10993082] [Full Text: https://doi.org/10.1038/35024111]
Andersen, G., Poterszman, A., Egly, J. M., Moras, D., Thierry, J.-C. The crystal structure of human cyclin H. FEBS Lett. 397: 65-69, 1996. [PubMed: 8941715] [Full Text: https://doi.org/10.1016/s0014-5793(96)01143-x]
Eki, T., Okumura, K., Abe, M., Kagotani, K., Taguchi, H., Murakami, Y., Pan, Z.-Q., Hanaoka, F. Mapping of the human genes encoding cyclin H (CCNH) and the CDK-activating kinase (CAK) assembly factor MAT1 (MNAT1) to chromosome bands 5q13.3-q14 and 14q23, respectively. Genomics 47: 115-120, 1998. [PubMed: 9465303] [Full Text: https://doi.org/10.1006/geno.1997.5053]
Fisher, R. P., Morgan, D. O. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell 78: 713-724, 1994. [PubMed: 8069918] [Full Text: https://doi.org/10.1016/0092-8674(94)90535-5]
Shiekhattar, R., Mermelstein, F., Fisher, R. P., Drapkin, R., Dynlacht, B., Wessling, H. C., Morgan, D. O., Reinberg, D. Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature 374: 283-287, 1995. [PubMed: 7533895] [Full Text: https://doi.org/10.1038/374283a0]