Cyclin K Explained

Cyclin-K is a protein that in humans is encoded by the CCNK gene.^{[1] [2]}

Function

The protein encoded by this gene is a member of the transcription cyclin family. These cyclins may regulate transcription through their association with and activation of cyclin-dependent kinases (CDKs) through conformational changes.^{[3] [4]} Activation of CDKs through their cyclin partner, creates kinase complexes that will activate target proteins through phosphorylation. Targeted proteins can then ultimately regulate decisions of a cell's progression within the cell cycle to occur. This gene product may be seen to play a dual role in both regulating CDK and RNA polymerase II (RNAP2) activities. Cyclin K only uses RNA recruitment to activate transcription.^[5]

Interactions

Cyclin K has been shown to interact with multiple CDKs including CDK9 and latest CDK12 and CDK13. Roles include helping to phosphorylate C-terminal domains of subunits of RNAP2.^[6] Cyclin K is most noted for its associated induction of processive elongation. Also, identified with G1 and S phase cyclin activity, however functions are not deeply understood.^[7]

Cyclin K also interacts with HIV nef protein.^[8] In the presence of overexpressed Nef protein, Cyclin k and CDK9 binding is induced, inhibiting the positive elongation factor of other CDK9 binding complexes, resulting in an inhibition of specific HIV-1 gene expression. CDK 13 may also be characterized to interact with HIV mRNA splicing, alongside Nef, and the underexpression of Gag and Env related proteins.^[9]

Cyclin K is indispensable for Leukemia growth. SETD1A, is also known to bind Cyclin K through its FLOS domain.^[10] The interaction is shown to be important to DNA damage response genes and for Leukemia proliferation.

Further reading

• Lin X, Taube R, Fujinaga K, Peterlin BM . P-TEFb containing cyclin K and Cdk9 can activate transcription via RNA . The Journal of Biological Chemistry . 277 . 19 . 16873–8 . May 2002 . 11884399 . 10.1074/jbc.M200117200 . free .
• Mori T, Anazawa Y, Matsui K, Fukuda S, Nakamura Y, Arakawa H . Cyclin K as a direct transcriptional target of the p53 tumor suppressor . Neoplasia . 4 . 3 . 268–74 . 2002 . 11988847 . 1531701 . 10.1038/sj.neo.7900235 .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . August 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . free .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . free .
• Baek K, Brown RS, Birrane G, Ladias JA . Crystal structure of human cyclin K, a positive regulator of cyclin-dependent kinase 9 . Journal of Molecular Biology . 366 . 2 . 563–73 . February 2007 . 17169370 . 1852425 . 10.1016/j.jmb.2006.11.057 .

Notes and References

1. Fu TJ, Peng J, Lee G, Price DH, Flores O . Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription . The Journal of Biological Chemistry . 274 . 49 . 34527–30 . December 1999 . 10574912 . 10.1074/jbc.274.49.34527 . free .
2. Web site: Entrez Gene: CCNK cyclin K.
3. Baek K, Brown RS, Birrane G, Ladias JA . Crystal structure of human cyclin K, a positive regulator of cyclin-dependent kinase 9 . Journal of Molecular Biology . 366 . 2 . 563–73 . February 2007 . 17169370 . 1852425 . 10.1016/j.jmb.2006.11.057 .
4. Greifenberg AK, Hönig D, Pilarova K, Düster R, Bartholomeeusen K, Bösken CA, Anand K, Blazek D, Geyer M . Structural and Functional Analysis of the Cdk13/Cyclin K Complex . Cell Reports . 14 . 2 . 320–31 . January 2016 . 26748711 . 10.1016/j.celrep.2015.12.025 . free . 11858/00-001M-0000-0029-567D-5 . free .
5. Kohoutek J, Blazek D . Cyclin K goes with Cdk12 and Cdk13 . Cell Division . 7 . 12 . April 2012 . 22512864 . 3348076 . 10.1186/1747-1028-7-12 . free .
6. Edwards MC, Wong C, Elledge SJ . Human cyclin K, a novel RNA polymerase II-associated cyclin possessing both carboxy-terminal domain kinase and Cdk-activating kinase activity . Molecular and Cellular Biology . 18 . 7 . 4291–300 . July 1998 . 9632813 . 109013 . 10.1128/mcb.18.7.4291 .
7. Edwards MC, Wong C, Elledge SJ . Human cyclin K, a novel RNA polymerase II-associated cyclin possessing both carboxy-terminal domain kinase and Cdk-activating kinase activity . Molecular and Cellular Biology . 18 . 7 . 4291–300 . July 1998 . 9632813 . 109013 . 10.1128/MCB.18.7.4291.
8. Khan SZ, Mitra D . Cyclin K inhibits HIV-1 gene expression and replication by interfering with cyclin-dependent kinase 9 (CDK9)-cyclin T1 interaction in Nef-dependent manner . The Journal of Biological Chemistry . 286 . 26 . 22943–54 . July 2011 . 21555514 . 3123062 . 10.1074/jbc.M110.201194 . free .
9. Berro R, Pedati C, Kehn-Hall K, Wu W, Klase Z, Even Y, Genevière AM, Ammosova T, Nekhai S, Kashanchi F . CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing . Journal of Virology . 82 . 14 . 7155–66 . July 2008 . 18480452 . 10.1128/JVI.02543-07 . 2446983 .
10. Hoshii T, Cifani P, Feng Z, Huang CH, Koche R, Chen CW, Delaney CD, Lowe SW, Kentsis A, Armstrong SA . A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response . Cell . 172 . 5 . 1007–1021.e17 . February 2018 . 29474905 . 10.1016/j.cell.2018.01.032 . 6052445.