KIN28, a yeast split gene coding for a putative protein kinase homologous to CDC28.

Simon, Michel; Séraphin, Bertrand; Faye, Gérard

doi:10.1002/j.1460-2075.1986.tb04553.x

Cited by 94 publications

(63 citation statements)

References 41 publications

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“…These kinases are found in separate complexes associated with transcriptional proteins, suggesting that they may have dierent roles (Maldonado et al, 1996;Rickert et al, 1996). These ®ndings are in support of previous genetic evidence that the yeast homologs of cyclin C/CDK8 and cyclin H/CDK7/p36, SRB10/SRB11 and KIN28/CCL1, respectively, have distinct functions (Kuchin et al, 1995;Liao et al, 1995;Simon et al, 1986;Valay et al, 1993). Together, these results suggest that these kinases play dierent roles in regulating the functions of the CTD and RNA polymerase II.…”

Section: Discussionsupporting

confidence: 86%

Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases

1999

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Phosphorylation of the carboxyl-terminal domain (CTD) of RNA polymerase II is important for basal transcriptional processes in vivo and for cell viability. Several kinases, including certain cyclin-dependent kinases, can phosphorylate this substrate in vitro. It has been proposed that dierential CTD phosphorylation by dierent kinases may regulate distinct transcriptional processes. We have found that two of these kinases, cyclin C/CDK8 and cyclin H/CDK7/p36, can speci®-cally phosphorylate distinct residues in recombinant CTD substrates. This dierence in speci®city may be largely due to their varying ability to phosphorylate lysine-substituted heptapeptide repeats within the CTD, since they phosphorylate the same residue in CTD consensus heptapeptide repeats. Furthermore, this substrate speci®city is re¯ected in vivo where cyclin C/ CDK8 and cyclin H/CDK7/p36 can dierentially phosphorylate an endogenous RNA polymerase II substrate. Several small-molecule kinase inhibitors have dierent speci®cities for these related kinases, indicating that these enzymes have diverse active-site conformations. These results suggest that cyclin C/CDK8 and cyclin H/CDK7/p36 are physically distinct enzymes that may have unique roles in transcriptional regulation mediated by their phosphorylation of speci®c sites on RNA polymerase II.

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Section: Discussionsupporting

confidence: 86%

Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases

1999

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“…In S. cerevisiae, where sophisticated genetic analysis can be readily combined with biochemistry to determine their biological roles, three CTD kinases have been identified to date: Kin28, the kinase subunit of TFIIH (8,12); Srb10, which is a component of the Pol II holoenzyme (31); and Ctk1, the catalytic subunit of the CTDK1 kinase complex (29). These three CTD kinases clearly have different functions in vivo: KIN28 is essential for viability (49), whereas srb10⌬ and ctk1⌬ strains are each viable yet display distinct mutant phenotypes (3,27,29,51,56). A recent hypothesis proposes that the functional differences between the kinases are not due to different catalytic activities or substrate preferences within the CTD repeats but instead are due to temporal differences in activity during the transcription cycle (18).…”

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confidence: 99%

Phosphorylation of the RNA Polymerase II Carboxy-Terminal Domain by the Bur1 Cyclin-Dependent Kinase

Murray

Udupa

Yao

et al. 2001

Molecular and Cellular Biology

122

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BUR1, which was previously identified by a selection for mutations that have general effects on transcription in Saccharomyces cerevisiae, encodes a cyclin-dependent kinase that is essential for viability, but none of its substrates have been identified to date. Using an unbiased biochemical approach, we have identified the carboxy-terminal domain (CTD) of Rpb1, the largest subunit of RNA polymerase II, as a Bur1 substrate. Phosphorylation of Rpb1 by Bur1 is likely to be physiologically relevant, since bur1 mutations interact genetically with rpb1 CTD truncations and with mutations in other genes involved in CTD function. Several genetic interactions are presented, implying a role for Bur1 during transcriptional elongation. These results identify Bur1 as a fourth S. cerevisiae CTD kinase and provide striking functional similarities between Bur1 and metazoan P-TEFb.The largest subunit of RNA polymerase II (Pol II), Rpb1, contains a highly conserved carboxy-terminal domain (CTD) that has a central role in transcriptional regulation in vivo (3, 11). The Rpb1 CTD consists of multiple repeats of the consensus heptapeptide sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser, which is repeated 26 times in Saccharomyces cerevisiae, 42 times in Drosophila melanogaster, and 52 times in humans and mice (9). Although the CTD is not required for RNA polymerase activity in promoter-independent assays, it is essential in vivo; deletion of the entire CTD in Drosophila and S. cerevisiae results in lethality, while truncation to 11 repeats in yeast confers conditional growth and promoter-specific transcriptional defects (36).Phosphorylation of the CTD is important for regulation of Pol II activity during the transcription cycle: unphosphorylated Pol II is preferentially recruited into the preinitiation complex (PIC) (33) and then becomes phosphorylated during the transition from initiation to elongation (28). CTD phosphorylation thus has both stimulatory and inhibitory roles; phosphorylation prior to PIC assembly inhibits initiation, while phosphorylation after PIC assembly stimulates promoter escape and elongation. Phosphorylation occurs primarily on serine 2 and serine 5 of the consensus CTD repeat, with serine 2-phosphorylated Rpb1 being enriched distally from the promoter and serine 5-phosphorylated Rpb1 being enriched at promoter-proximal regions (26). Hyperphosphorylation of the CTD is also linked to other essential events during mRNA synthesis, including recruitment of mRNA modification enzymes and pre-mRNA splicing factors (reviewed in reference 50).The importance of CTD phosphorylation for Pol II regulation has prompted efforts to identify the kinases and phosphatases that determine the CTD phosphorylation state. Several kinases capable of phosphorylating the CTD in vitro have been identified in Drosophila, human, and rodent cell extracts (reviewed in reference 11), but it is not clear whether they all function as CTD kinases in vivo. In S. cerevisiae, where sophisticated genetic analysis can be readily combined with biochemistry to de...

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“…In addition to its CAK activity, the Cdk7 complex forms part of transcription factor IIH (TFIIH) and phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (15,16). In budding yeast, the closest relative to Cdk7 is Kin28p (17,18). Kin28p associates with a cyclin (Ccl1p) (19) and an assembly factor (Tfb3/Rig2) (20) and exhibits CTD kinase activity (21) as a portion of yeast TFIIH.…”

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confidence: 99%

Comparison of Cak1p-like Cyclin-dependent Kinase-activating Kinases

Tsakraklides

Solomon

2002

Journal of Biological Chemistry

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Cyclin-dependent kinases (cdks) coordinate progression through the eukaryotic cell cycle and require phosphorylation by a cdk-activating kinase (CAK) for full activity. In most eukaryotes Cdk7 is the catalytic subunit of a heterotrimeric CAK (Cdk7-cyclin H-Mat1) that is also involved in transcription as part of the transcription factor IIH complex. The Saccharomyces cerevisiae CAK, Cak1p, is a monomeric protein kinase with an atypical sequence and unusual biochemical properties compared with trimeric CAKs and other protein kinases. We sought to determine whether these properties were shared by a small group of monomeric CAKs that can function in place of CAK1 in S. cerevisiae. We found that Schizosaccharomyces pombe Csk1, Candida albicans Cak1, and Arabidopsis thaliana Cak1At, like Cak1p, all displayed a preference for cyclin-free cdk substrates, were insensitive to the protein kinase inhibitor 5 -fluorosulfonylbenzoyladenosine (FSBA), and were insensitive to mutation of a highly conserved lysine residue found in the nucleotide binding pocket of all protein kinases. The S. pombe and C. albicans kinases also resembled Cak1p in their kinetics of nucleotide and protein substrate utilization. Conservation of these unusual properties in fungi and plants points to shared evolutionary requirements not met by Cdk7 and raises the possibility of developing antifungal agents targeting CAKs.

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KIN28, a yeast split gene coding for a putative protein kinase homologous to CDC28.

Cited by 94 publications

References 41 publications

Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases

Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases

Phosphorylation of the RNA Polymerase II Carboxy-Terminal Domain by the Bur1 Cyclin-Dependent Kinase

Comparison of Cak1p-like Cyclin-dependent Kinase-activating Kinases

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