- CDK7 pathway
CDK7 is a
cyclin-dependent kinase shown to be not easily classified. CDK7 is both a CDK-activating kinase (CAK) and a component of the generaltranscription factor TFIIH.Introduction
An intricate network of
cyclin-dependent kinase s (CDKs) are organized in a pathway to ensure that each cell accurately replicates itsDNA andsegregate it equally between the two daughter cells [Morgan DO. (2007). The Cell Cycle: Principles of Control. New Science Press Ltd: London, UK] . One CDK–the CDK7 complex–cannot be so easily classified. CDK7 is both a CDK-activating kinase (CAK), whichphosphorylate s cell-cycle CDKs within the activation segment (T-loop), and a component of the generaltranscription factor TFIIH, which phosphorylates the C-terminal domain (CTD) of the largest subunit of Pol II [Harper, J. W., Elledge, S. J., Keyomarski, K., Dynlacht, B., Tsai, L.-H., Zhang, P., Dobrowolski, S., Bai, C., Connell-Crowley, L., Swindell, E. et al. (1995). Inhibition of cyclin-dependent kinases by p21. Mol. Biol. Cell 6, 387-400] . A proposed mode of CDK7 inhibition is thephosphorylation of cyclin H by CDK7 itself [Lolli, G., Lowe, E. D., Brown, N. R. and Johnson, L. N. (2004). The crystal structure of human CDK7 and its protein recognition properties. Structure 12, 2067-2079] or by another kinase [Akoulitchev, S. and Reinberg, D. (1998). The molecular mechanism of mitotic inhibition of TFIIH is mediated by phosphorylation of CDK7. Genes Dev. 12, 3541-3550] .The T-loop
In order to be active, most CDKs require not only a cyclin partner but also phosphorylation at one particular site, which corresponds to Thr161 in human CDK1, and which is located within the so-called T-loop of kinase subdomain VIII [Morgan DO: Principles of CDK regulation. Nature 1995, 374:131-134] [Solomon MJ: The function(s) of CAK, the p34cdc2 activating kinase. Trends Biochem Sci 1994,19:496-500] . CDKl, CDK2 and CDK4 all require T-loop phosphorylation for maximum activity [Connell-Cowley L, Solomon MJ, Wei N, Harper JW: Phosphorylation independent activation of human cyclindependent kinase 2 by cyclin A in vitro. Mol Biol Cell 1993, 4:79-92] [Matsuoka M, Kate JY, Fisher RP, Mor of cyclin-dependent kinase 4 (cdk4 by B mouse M015-an associated klnase. Mol Cell Biol 1994, 14:7265-7275.] .
Dual activity
An entirely new perspective on CDK7 function was opened when CDK7 was identified as a subunit of transcription factor IIH (TFIIH) and shown to phosphorylate the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) [Roy R, Adamczewski JP, Seroz T, Vermeulen W, Tassan JP, Schaeffer L, Nigg EA, Hoejimakers JHJ, Egly JM: The MO15 cell cycle kinase is associated with the TFIIH transcription-DNA repair factor. Cell 1994, 79:1093-1101] . TFIIH is a multiprotein complex required not only for class II transcription but also for nucleotide-excision repair [Seroz T, Hwang JR, Moncollin V, Egly JM: TFIIH: a link between transcription,
DNA repair andcell cycle regulation. Gun Opin Gener Dev 1995, 5:217-221] . Its associated CTD-kinase activity is considered important for the promoter-clearance step of transcription, but the precise structural consequences of thephosphorylation of the CTD remain the subject of debate [Dahmus ME: The role of multisite phosphorylatlon in the regulation of RNA polymerase II activity. Prog Nucleic Acid Res Mol Biol 1994, 48: 143-179] . Cyclin H and MAT1 are also present in TFIIH [Shiekhattar R, Mermelstein F, Fisher R, Drapkin R, Dynlacht B, Wessling HC, Morgan DO, Reinberg D: Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature 1995, 374:203-287] , and it is not known what, if anything, distinguishes the TFIIH-associated form of CDK7 from the quantitatively predominant free form. Whether CDK7 really displays dual-substrate specificity remains to be further explored, but there is no question that the CDK7-cyclin H-MAT1 complex is able tophosphorylate both the T-loop of CDKs and the YSPTSPS (single-letter code foramino acids ) repeats of theRNAP II CTD "in vitro".HIV latency
It has been demonstrated that TFIIH is a rate-limiting factor for
HIV transcription in unactivatedT-cells by using a combination of in vivo ChIP experiments and cell-free transcription studies [Kim YK et al., Recruitment of TFIIH to theHIV LTR is a rate-limiting step in the emergence of HIV from latency. EMBO J. 2006 Aug 9;25(15):3596-604] . The ability ofNFkB to rapidly recruit TFIIH duringHIV activation inT-cells is an unexpected discovery; however, there are several precedents in the literature of cellular genes that are activated through the recruitment of TFIIH. In an early and influential paper [Blau J , Xiao H , McCracken S , O'Hare P , Greenblatt J , Bentley D (1996) Three functional classes of transcriptional activation domains. Mol Cell Biol 16: 2044–2055] , demonstrated that type I activators such as Sp1 and CTF, which were able to support initiation but were unable to support efficient elongation, were also unable to bind TFIIH. By contrast, type II activators such as VP16, p53 and E2F1, which supported both initiation and elongation, were able to bind to TFIIH. In one of the most thoroughly characterized transcription systems [Spilianakis C , Kretsovali A , Agalioti T , Makatounakis T , Thanos D , Papamatheakis J (2003) CIITA regulates transcription onset via Ser5-phosphorylation of RNA Pol II. EMBO J 22: 5125–5136] , have studied the temporal order of recruitment of transcription factors during the activation of the major histocompatibility class II (MHC II ) DRA gene byIFN -gamma. Following induction of the CIITA transcription factor byIFN -gamma, there was recruitment of both CDK7 and CDK9 causingRNAP CTD phosphorylation and elongation. Finally, Nissen and Yamamoto (2000) [Nissen RM , Yamamoto KR (2000) The glucocorticoid receptor inhibits NFkB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev 14: 2314–2329] in their studies of the activation of the IL-8 and ICAM-1 promoters observed enhanced CDK7 recruitment andRNAP II CTDphosphorylation in response toNFkB activation by TNF.References
See also
*
Cyclin
*Cell cycle
*Wee (cell cycle)
*Cell cycle checkpoint
Wikimedia Foundation. 2010.