8r99

Structural highlights

Function

CDK7_HUMAN Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. Cyclin-dependent kinases (CDKs) are activated by the binding to a cyclin and mediate the progression through the cell cycle. Each different complex controls a specific transition between 2 subsequent phases in the cell cycle. Required for both activation and complex formation of CDK1/cyclin-B during G2-M transition, and for activation of CDK2/cyclins during G1-S transition (but not complex formation). CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Phosphorylates SPT5/SUPT5H, SF1/NR5A1, POLR2A, p53/TP53, CDK1, CDK2, CDK4, CDK6 and CDK11B/CDK11. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation, thus regulating cell cycle progression. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminus domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Phosphorylation of POLR2A in complex with DNA promotes transcription initiation by triggering dissociation from DNA. Its expression and activity are constant throughout the cell cycle. Upon DNA damage, triggers p53/TP53 activation by phosphorylation, but is inactivated in turn by p53/TP53; this feedback loop may lead to an arrest of the cell cycle and of the transcription, helping in cell recovery, or to apoptosis. Required for DNA-bound peptides-mediated transcription and cellular growth inhibition.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]}

References

1. ↑ Ko LJ, Shieh SY, Chen X, Jayaraman L, Tamai K, Taya Y, Prives C, Pan ZQ. p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner. Mol Cell Biol. 1997 Dec;17(12):7220-9. PMID:9372954
2. ↑ Schneider E, Montenarh M, Wagner P. Regulation of CAK kinase activity by p53. Oncogene. 1998 Nov 26;17(21):2733-41. PMID:9840937 doi:10.1038/sj.onc.1202504
3. ↑ Tirode F, Busso D, Coin F, Egly JM. Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7. Mol Cell. 1999 Jan;3(1):87-95. PMID:10024882
4. ↑ Garrett S, Barton WA, Knights R, Jin P, Morgan DO, Fisher RP. Reciprocal activation by cyclin-dependent kinases 2 and 7 is directed by substrate specificity determinants outside the T loop. Mol Cell Biol. 2001 Jan;21(1):88-99. PMID:11113184 doi:10.1128/MCB.21.1.88-99.2001
5. ↑ Larochelle S, Batliner J, Gamble MJ, Barboza NM, Kraybill BC, Blethrow JD, Shokat KM, Fisher RP. Dichotomous but stringent substrate selection by the dual-function Cdk7 complex revealed by chemical genetics. Nat Struct Mol Biol. 2006 Jan;13(1):55-62. Epub 2005 Dec 4. PMID:16327805 doi:http://dx.doi.org/10.1038/nsmb1028
6. ↑ Larochelle S, Merrick KA, Terret ME, Wohlbold L, Barboza NM, Zhang C, Shokat KM, Jallepalli PV, Fisher RP. Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol Cell. 2007 Mar 23;25(6):839-50. PMID:17386261 doi:http://dx.doi.org/10.1016/j.molcel.2007.02.003
7. ↑ Lolli G, Johnson LN. Recognition of Cdk2 by Cdk7. Proteins. 2007 Jun 1;67(4):1048-59. PMID:17373709 doi:http://dx.doi.org/10.1002/prot.21370
8. ↑ Lewis AE, Rusten M, Hoivik EA, Vikse EL, Hansson ML, Wallberg AE, Bakke M. Phosphorylation of steroidogenic factor 1 is mediated by cyclin-dependent kinase 7. Mol Endocrinol. 2008 Jan;22(1):91-104. Epub 2007 Sep 27. PMID:17901130 doi:http://dx.doi.org/10.1210/me.2006-0478
9. ↑ Akhtar MS, Heidemann M, Tietjen JR, Zhang DW, Chapman RD, Eick D, Ansari AZ. TFIIH kinase places bivalent marks on the carboxy-terminal domain of RNA polymerase II. Mol Cell. 2009 May 15;34(3):387-93. doi: 10.1016/j.molcel.2009.04.016. PMID:19450536 doi:http://dx.doi.org/10.1016/j.molcel.2009.04.016
10. ↑ Yang WH, Heaton JH, Brevig H, Mukherjee S, Iniguez-Lluhi JA, Hammer GD. SUMOylation inhibits SF-1 activity by reducing CDK7-mediated serine 203 phosphorylation. Mol Cell Biol. 2009 Feb;29(3):613-25. doi: 10.1128/MCB.00295-08. Epub 2008 Nov, 17. PMID:19015234 doi:http://dx.doi.org/10.1128/MCB.00295-08
11. ↑ Glover-Cutter K, Larochelle S, Erickson B, Zhang C, Shokat K, Fisher RP, Bentley DL. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol Cell Biol. 2009 Oct;29(20):5455-64. Epub 2009 Aug 10. PMID:19667075 doi:http://dx.doi.org/MCB.00637-09
12. ↑ Lolli G. Binding to DNA of the RNA-polymerase II C-terminal domain allows discrimination between Cdk7 and Cdk9 phosphorylation. Nucleic Acids Res. 2009 Mar;37(4):1260-8. doi: 10.1093/nar/gkn1061. Epub 2009 Jan, 9. PMID:19136461 doi:http://dx.doi.org/10.1093/nar/gkn1061
13. ↑ Lv X, Wang J, Dong Z, Lv F, Qin Y. DNA-Bound peptides control the mRNA transcription through CDK7. Peptides. 2009 Apr;30(4):681-8. doi: 10.1016/j.peptides.2008.11.008. Epub 2008, Nov 24. PMID:19071173 doi:http://dx.doi.org/10.1016/j.peptides.2008.11.008
14. ↑ Timofeev O, Cizmecioglu O, Settele F, Kempf T, Hoffmann I. Cdc25 phosphatases are required for timely assembly of CDK1-cyclin B at the G2/M transition. J Biol Chem. 2010 May 28;285(22):16978-90. doi: 10.1074/jbc.M109.096552. Epub, 2010 Apr 1. PMID:20360007 doi:http://dx.doi.org/10.1074/jbc.M109.096552