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Gene Review

KIN28  -  TFIIH complex serine/threonine-protein...

Saccharomyces cerevisiae S288c

Synonyms: D2330, Serine/threonine-protein kinase KIN28, YDL108W
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High impact information on KIN28

  • Notably, inactivation of Kin28p causes a loss of both Ser5 phosphorylation and the loop conformation [1].
  • TBP association depends on the Pol II holoenzyme component Srb4, but not on the Kin28 subunit of the transcription factor TFIIH, even though both proteins are generally required for transcription [2].
  • In yeast, the major CTD kinase is a subunit of the general transcription factor TFIIH, and is encoded by an essential gene, KIN28 [3].
  • We also show that transcription of these Kin28-independent genes is independent of Srb4 and Srb6, critical components of the CTD-associated transcriptional mediator complex [3].
  • These results indicate that there are at least two distinct pathways for transcriptional activation: one is dependent on Kin28 and the mediator complex, and the other is not [3].

Biological context of KIN28

  • In this study, we used a thermosensitive allele of KIN28 and a hemagglutinin epitope-tagged Kin28 protein to investigate Kin28 function in transcription and in the cell cycle [4].
  • The KIN28 gene is required both for RNA polymerase II mediated transcription and phosphorylation of the Rpb1p CTD [5].
  • We also found that environmental conditions for meiosis finely regulate the transcript levels of KIN28 and CCL1, such that nitrogen starvation first elevates them but subsequent alkalization of medium decreases them [6].
  • The KIN28 gene failed to complement cdc28 mutations and was shown to be essential for cell proliferation [7].
  • KIN28, a yeast split gene coding for a putative protein kinase homologous to CDC28 [7].

Associations of KIN28 with chemical compounds

  • We have isolated, in yeast, a nuclear gene named KIN28 which presents significant sequence homology with the cell-division-cycle CDC28 gene, with members of the protein-tyrosine kinase family (src, erb, abl, epidermal growth factor, etc.) and those of the family of protein kinases phosphorylating serine and threonine [7].
  • In addition to the previously known substrate, the Pol II CTD, it was found that Kin28 phosphorylates two subunits of Mediator and Srb10 targets two subunits of TFIID for phosphorylation [8].
  • In support of a role for Rad6-dependent H2B ubiquitylation in transcription elongation, we find that ubH2B levels are dramatically reduced in strains bearing mutations of the Pol II C-terminal domain (CTD) and abolished by inactivation of Kin28, the serine 5 CTD kinase that promotes the transition from initiation to elongation [9].
  • Using purified proteins we have determined that the subunits of TFIIK are sufficient for Mediator to enhance Kin28 CTD kinase activity and that Mediator enhances phosphorylation of a glutathione S-transferase-CTD fusion protein, despite the absence of multiple Mediator and/or TFIIH interactions with polymerase [10].
  • Hint, histidine triad nucleotide-binding protein, is a universally conserved enzyme that hydrolyzes AMP linked to lysine and, in yeast, functions as a positive regulator of the RNA polymerase II C-terminal domain kinase, Kin28 [11].

Physical interactions of KIN28

  • The Kin28 protein kinase interacts physically and genetically with cyclin Ccl1 [12].
  • In this report, we provide evidence that Ssu72 is a phosphatase that physically interacts with the CTD kinase Kin28 and functionally interacts with the CTD phosphatase Fcp1 [13].

Enzymatic interactions of KIN28

  • In addition, we have found that Kin28 phosphorylates Mediator subunit Med4 in an assay, including purified holo-TFIIH, and either Mediator or recombinant Med4 alone [10].

Other interactions of KIN28

  • Cak1 is required for Kin28 phosphorylation and activation in vivo [14].
  • The genetic interaction between KIN28 and the CDC37 cell division cycle gene suggests that a connection exists between the activity of CDK-Kin28p and cell-cycle progression [5].
  • Kin28p, associated with cyclin Ccl1p, is a putative cyclin-dependent kinase (CDK) of the p34cdc2 family in Saccharomyces cerevisiae [5].
  • Moreover, cells containing kin28(T162A) and a conditional allele of TFB3 (the ortholog of the mammalian MAT1 protein, an assembly factor for MO15 and cyclin H) are severely compromised and display a significant further reduction in Kin28p activity [15].
  • Thus in yeast cells, TBP association with promoters occurs in concert with the Pol II holoenzyme, activator-dependent recruitment of the Pol II machinery occurs at the vast majority of promoters, and Kin28 acts after the initial recruitment [2].


  1. Gene loops juxtapose promoters and terminators in yeast. O'Sullivan, J.M., Tan-Wong, S.M., Morillon, A., Lee, B., Coles, J., Mellor, J., Proudfoot, N.J. Nat. Genet. (2004) [Pubmed]
  2. Binding of TBP to promoters in vivo is stimulated by activators and requires Pol II holoenzyme. Kuras, L., Struhl, K. Nature (1999) [Pubmed]
  3. Transcriptional activation independent of TFIIH kinase and the RNA polymerase II mediator in vivo. Lee, D., Lis, J.T. Nature (1998) [Pubmed]
  4. KIN28 encodes a C-terminal domain kinase that controls mRNA transcription in Saccharomyces cerevisiae but lacks cyclin-dependent kinase-activating kinase (CAK) activity. Cismowski, M.J., Laff, G.M., Solomon, M.J., Reed, S.I. Mol. Cell. Biol. (1995) [Pubmed]
  5. The KIN28 gene is required both for RNA polymerase II mediated transcription and phosphorylation of the Rpb1p CTD. Valay, J.G., Simon, M., Dubois, M.F., Bensaude, O., Facca, C., Faye, G. J. Mol. Biol. (1995) [Pubmed]
  6. A transcriptional autoregulatory loop for KIN28-CCL1 and SRB10-SRB11, each encoding RNA polymerase II CTD kinase-cyclin pair, stimulates the meiotic development of S. cerevisiae. Ohkuni, K., Yamashita, I. Yeast (2000) [Pubmed]
  7. KIN28, a yeast split gene coding for a putative protein kinase homologous to CDC28. Simon, M., Seraphin, B., Faye, G. EMBO J. (1986) [Pubmed]
  8. Two cyclin-dependent kinases promote RNA polymerase II transcription and formation of the scaffold complex. Liu, Y., Kung, C., Fishburn, J., Ansari, A.Z., Shokat, K.M., Hahn, S. Mol. Cell. Biol. (2004) [Pubmed]
  9. Histone H2B ubiquitylation is associated with elongating RNA polymerase II. Xiao, T., Kao, C.F., Krogan, N.J., Sun, Z.W., Greenblatt, J.F., Osley, M.A., Strahl, B.D. Mol. Cell. Biol. (2005) [Pubmed]
  10. Mutual targeting of mediator and the TFIIH kinase Kin28. Guidi, B.W., Bjornsdottir, G., Hopkins, D.C., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Myers, L.C. J. Biol. Chem. (2004) [Pubmed]
  11. Biochemical, crystallographic, and mutagenic characterization of hint, the AMP-lysine hydrolase, with novel substrates and inhibitors. Krakowiak, A., Pace, H.C., Blackburn, G.M., Adams, M., Mekhalfia, A., Kaczmarek, R., Baraniak, J., Stec, W.J., Brenner, C. J. Biol. Chem. (2004) [Pubmed]
  12. Ccl1, a cyclin associated with protein kinase Kin28, controls the phosphorylation of RNA polymerase II largest subunit and mRNA transcription. Valay, J.G., Dubois, M.F., Bensaude, O., Faye, G. C. R. Acad. Sci. III, Sci. Vie (1996) [Pubmed]
  13. Ssu72 is a phosphatase essential for transcription termination of snoRNAs and specific mRNAs in yeast. Ganem, C., Devaux, F., Torchet, C., Jacq, C., Quevillon-Cheruel, S., Labesse, G., Facca, C., Faye, G. EMBO J. (2003) [Pubmed]
  14. Cak1 is required for Kin28 phosphorylation and activation in vivo. Espinoza, F.H., Farrell, A., Nourse, J.L., Chamberlin, H.M., Gileadi, O., Morgan, D.O. Mol. Cell. Biol. (1998) [Pubmed]
  15. Activating phosphorylation of the Kin28p subunit of yeast TFIIH by Cak1p. Kimmelman, J., Kaldis, P., Hengartner, C.J., Laff, G.M., Koh, S.S., Young, R.A., Solomon, M.J. Mol. Cell. Biol. (1999) [Pubmed]
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