Department of Cellular Biology, University of Georgia
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Abstract |
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Introduction |
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In both the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe, a single CDK (Cdc28 and Cdc2, respectively), is responsible for catalyzing all major cell cycle transitions (Morgan 1997
). In higher eukaryotes, there has been an expansion in the number of CDKs that regulate the cell cycle, with five cell cycle CDKs in mammals. This expansion allowed the specialization of CDKs for particular cell cycle transitions/functions: CDK4, CDK6, and CDK3 regulate G1 phase progression and entry into S phase; CDK2 is required for entry into S phase and DNA replication; and CDK1 (CDC2) is required for mitosis (van den Heuvel and Harlow 1993
; King, Jackson, and Kirschner 1994
; Sherr 1994
; Stillman 1996
; Morgan 1997
).
In S. cerevisiae, five CDKs function to regulate transcription. Three of these CDKs, Kin28, Srb10, and Ctk1, regulate mRNA synthesis by phosphorylating the carboxyl-terminal domain (CTD) of RNA Polymerase II (Valay et al. 1995
; Liao et al. 1995
; Lee and Greenleaf 1991
; Sterner et al. 1995
). Sgv1 regulates transcription, potentially also as a CTD kinase, as its ortholog CDK9 functions as a CTD kinase (Prelich and Winston 1993
; Reines, Conaway, and Conaway 1999
). Finally, Pho85 functions to inhibit gene transcription in response to phosphate (Lenburg and O'Shea 1996
). Pho85 also has a secondary role in promoting cell cycle progression, as it is required for G1-to-S phase progression when the G1 cyclins Cln1 and Cln2 are missing (Espinoza et al. 1994
; Measday et al. 1994
).
CDK activity is tightly regulated through four mechanisms: (1) binding by activating cyclins, (2) binding by inhibitory cyclin-dependent kinase inhibitors (CKIs), (3) inhibitory phosphorylation of the CDK, and (4) activating phosphorylation of the CDK. The activating phosphorylation is catalyzed by a CDK-activating kinase (CAK) (Kaldis 1999
). CAK phosphorylates a conserved threonine or serine residue in CDKs (throughout this paper, this site will be referred to as Thr 160, which corresponds to the position in CDK2, although the exact amino acid position varies among the kinases). This phosphorylation stabilizes cyclin-CDK interaction and enhances substrate binding (Russo, Jeffrey, and Pavletich 1996
). CDKs depend on CAK phosphorylation for activation, and a loss of CAK activity causes cell cycle arrest (Espinoza et al. 1996
; Kaldis, Sutton, and Solomon 1996
; Thuret et al. 1996
; Larochelle et al. 1998
; Lee et al. 1999
).
In S. cerevisiae, Cak1/Civ1 is the sole essential CAK for both the cell cycle CDK Cdc28 and the transcriptional CDK Kin28 (Kaldis, Sutton, and Solomon 1996
; Thuret et al. 1996
; Espinoza et al. 1998
). It is a distant member of the CDK family and has diverged considerably not only from other CDKs, but also from other kinases. Cak1 is fully active without a cyclin partner or activating phosphorylation (Kaldis, Sutton, and Solomon 1996
; Thuret et al. 1996
). Furthermore, it lacks the consensus GXGXXG motif that is implicated in nucleotide binding for all classes of protein kinase (Hanks and Hunter 1995
). Currently, only two other kinases have been found that also lack the entire GXGXXG motif, Mik1 and Vps15 (Kaldis 1999
). No CAK1 ortholog has been reported in any other organism to date.
The budding yeast CDK Kin28 possesses no CAK activity in vitro or in vivo (Feaver et al. 1994
; Cismowski et al. 1995
; Valay et al. 1995
). However, in metazoans, the Kin28 ortholog CDK7/p40MO15 was identified as a CAK based on its ability to phosphorylate and activate CDK1 in vitro (Poon et al. 1993
; Solomon, Harper, and Shuttleworth 1993
; Darbon et al. 1994
; Tassan et al. 1994
). In Drosophila melanogaster, a Cdk7 temperature-sensitive mutant was found to be defective for CAK activity for the cdc2/Cyclin A and cdc2/Cyclin B complexes (Larochelle et al. 1998
). The conclusion that Cdk7 was the in vivo CAK for cdc2 was tempered by the fact that Cdk7 also functions as a transcriptional activator, and therefore the loss of CAK activity could have resulted from an inability to synthesize the true CAK. The D. melanogaster Cdk7 mutations did not affect the activating phosphorylation of cdc2c (Cdk2) in vivo, suggesting that there are additional CAKs in metazoans (Larochelle et al. 1998
). CDK7 binds Cyclin H and requires activating phosphorylation (Kaldis 1999
). The in vivo CAK for CDK7 is currently not known.
In S. pombe, the Kin28 ortholog Mcs6/Mop1/Crk1 is a CAK for the cell cycle CDK, Cdc2 (Buck, Russell, and Millar 1995
; Damagnez, Makela, and Cottarel 1995
). A divergent CDK family member, Csk1, works redundantly with Mcs6 to activate Cdc2 (Lee et al. 1999
). Csk1 also phosphorylates Mcs6 on the consensus activating site Ser 165 (Molz and Beach 1993
; Hermand et al. 1998
).
Cell cycle regulators are largely conserved among eukaryotes (Pines 1995
). As Cak1 is an essential cell cycle regulator in budding yeast, it is perplexing that no CAK1 ortholog has been found in any other organisms. Similarly, no ortholog of fission yeast csk1 has been reported. Since the metazoan CAK CDK7 does not appear to be sufficient for the activation of all CDKs (Larochelle et al. 1998
), and CDK7 itself needs activating phosphorylation, it is likely that there exists an unidentified metazoan CAK(s).
The genome sequence of Caenorhabditis elegans is essentially complete (C. elegans Sequencing Consortium 1998
), allowing a comprehensive analysis of a metazoan genome. Further, the genome of D. melanogaster has also been sequenced (Adams et. al. 2000). We identified 13 D. melanogaster and 14 C. elegans extended CDK family members. We undertook a phylogenetic analysis of the extended CDK family in budding yeast, fission yeast, and metazoans to provide insight into the evolution of the CDK family and to address whether an ortholog of CAK1 could be identified in metazoans.
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Materials and Methods |
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Phylogenetic Analysis
The neighbor-joining (NJ) (Saitou and Nei 1987
) and maximum-likelihood (ML) methods were used to create phylogenies. For NJ analyses, a distance matrix of the data set, using the JTT model, was created with the ProtML program of MOLPHY, version 2.3 (Adachi and Hasegawa 1996
). The matrix was used to create trees with the NEIGHBOR program of the PHYLIP package (Felsenstein 1993
), using random order of addition of taxa. Bootstrap values were obtained from 1,000 replicates.
Another JTT distance matrix was calculated using a model of rate heterogeneity among sites with eight rates following a gamma distribution plus one invariable rate using the PUZZLE program (Strimmer and von Haeseler 1996
) with exact parameter estimates of the gamma distribution parameter alpha and the fraction of invariable sites. The distance matrix was analyzed with the NEIGHBOR program (Felsenstein 1993
). Bootstrap values were obtained from 100 replicates.
An ML analysis was performed with the ProtML program of MOLPHY, version 2.3 (Adachi and Hasegawa 1996
). Input trees derived from Star Decomposition searches (ProtML program) or NJ trees were optimized by local branch rearrangement (LBR) analysis using the JTT model (Adachi and Hasegawa 1996
). We observed that LBRs of NJ input trees always gave higher likelihood phylogenies than those obtained using Star Decomposition input trees. Bootstrap probabilities were created by ProtML LBR analysis of 100 input data set resamplings created with the SeqBoot program (Felsenstein 1993
) using their associated NJ trees as input.
Relative apparent synapomorphy analysis (RASA) was applied using the RASA, version 2.3, package (Lyons-Weiler, Hoelzer, and Tausch 1996
; Lyons-Weiler and Hoelzer 1997
; Lyons-Weiler 1999
). After signal content analysis, a taxon variance analysis was used to detect taxa that manifested the hallmarks of long-branch attraction (Lyons-Weiler 1999
).
The removal of fast-evolving characters was accomplished according to the S-F method as described by Brinkmann and Philippe (1999)
. The substitution step was calculated with PAUP, version 4.0.b2a (Swofford 1993
), as described (Brinkmann and Philippe 1999
).
Molecular Experiments
An H01G02.2 cDNA was isolated by PCR from a cDNA library (provided by R. Barstead) using primers designed to amplify the coding region of H01G02.2, predicted by the C. elegans Genome Consortium (the Sanger Centre, Cambridge, and the Genome Sequencing Center at the Washington University School of Medicine, St. Louis, Mo.). The H01G02.2 cDNA was cloned into the pBluescript SKII+ plasmid (Stratagene) and sequenced to confirm the absence of PCR-induced mutations. Sense and antisense H01G02.2 RNAs were synthesized using the Megascript T7 and T3 kits according to the manufacturer's instructions (Ambion). Sense and antisense RNAs were annealed to create double-stranded RNA by heating to 93°C for 30 s, followed by twenty-five 30-s incubations at 2° decrements for each incubation. H01G02.2 dsRNA was injected into young adult C. elegans hermaphrodites at a concentration of 0.5 to 1 mg/ml. F1 progeny from injected mothers were scored for abnormalities.
To test whether H01G02.2 could complement cak1/civ1 mutants, an H01G02.2 cDNA was subcloned into the GAL1 promoter yeast expression plasmid pYes2 (Invitrogen). The H01G02.2/pYes2 plasmid and the pYes2 plasmid vector control were transformed by electroporation into the cak1-22 mutant strain SY143 (cak1::HIS3 [LEU2/cen-cak1-22],ade2, his3, leu2, can1, ura3, trp1, ssd1) (Kaldis, Sutton, and Solomon 1996
) and the civ1-4 mutant strain GF2351 (civ1-4, ura3, leu2, trp1, lys2, ade2, ade3) (Thuret et al. 1996
). The growth of strain SY143 (cak1-22) and strain GF2351 (civ1-4) was scored at 25°C (permissive temperature) and 37°C (nonpermissive temperature) on minimal media plates supplemented with 20 mg/ml galactose (to induce the GAL1 promoter).
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Results |
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Phylogenetic Analysis
The evolutionary rates of the yeast, D. melanogaster (D.m.), C. elegans (C.e.),and human (H.s.) CDK family members were expected to be different. We therefore chose to perform our phylogenetic analysis with the ML method and the NJ distance method (Felsenstein 1981
; Saitou and Nei 1987
). These methods are less likely to be misled than parsimony or compatibility methods when the evolutionary rates differ among taxa (Felsenstein 1978
; Saitou and Imanishi 1989
). When taxa have dissimilar rates of substitutions, incorporating the differential rate of character changes at given sites by fitting the amino acid data set to gamma rate distributions facilitates a more accurate phylogeny (Yang 1996
). We therefore used gamma-corrected distances for the NJ phylogeny.
The ML and gamma-corrected NJ methods both produced 10 clades for the CDKs (fig. 2 ). Seven of the clades for both methods contain both yeast and metazoan members and therefore represent ancestral clades. We will refer to these clades by their S. cerevisiae members, except for the clade containing only fission yeast BC18H10.15. Two of the clades, the CDK4/CDK6 clade and the KKIALRE clade, contain only metazoan members.
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The use of gamma-corrected distances can minimize or negate long-branch attraction (Swofford et al. 1996
). However, the RASA program is currently only capable of analyzing unweighted data sets (Lyons-Weiler 1999
), and therefore we could not determine if our use of gamma-corrected distances sufficiently minimized the potential for long-branch attraction. An alternative method to minimize potential long-branch attraction is to employ the theoretical framework of the S-F method of Brinkmann and Philippe (1999)
, in which fast-evolving sites are removed from the data set and phylogenetic relationships are determined based on slow-evolving sites. Fast-evolving sites with multiple substitutions that occurred only within a given taxon are essentially devoid of phylogenetic content and can act to obscure the true phylogeny.
To perform the S-F analysis, we created 17 data sets, S1S17, reflecting the sequential addition of faster-evolving character groups onto the slowest-evolving (S1) data set. RASA analysis indicated that all of the data sets still had significant Ftv scores for CAK1 and csk1 (data not shown). Both CAK1 and csk1 are notable for having changes in sites that are largely invariant. These changes are concentrated in the S1 and S2 data sets, which contain 16 of 34 positions in which either Cak1 or Csk1 have differences relative to an invariant amino acid in the rest of the CDK family taxa. The effect of these differences from a nearly invariant consensus is to make CAK1 and csk1 more dissimilar relative to other taxa and contribute to the potential problem of long-branch attraction. The S1 and S2 groups were removed from the S3S17 data sets to produce S3-3S3-17 data sets. Data sets S3-8S3-17 still had significant CAK1 and csk1 Ftv scores, while data sets S3-3S3-7 did not have significant Ftv scores for any taxa (data not shown). Data sets S3-4S3-7 retained significant association between CAK1 and csk1, with bootstrap support values of 90%99% (fig. 3 ). Data set S3-3 did not have sufficient phylogenetic information to resolve the clades (data not shown). Therefore, the results of both the gamma-corrected phylogenies and the S-F reduced character phylogenies suggest that the CAK1-csk1 association is not due to the effects of long-branch attraction.
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Experiments in our laboratory have failed to support a role for H01G02.2 as a CAK. After inactivating the H01G02.2 gene in C. elegans using double-stranded RNA-mediated interference (RNAi) (Fire et al. 1998
), we observed variable hyperdermal defects that were not interpretable as cell cycle arrest (data not shown). To test for redundancy of CAK function, we inactivated both H01G02.2 and cdk-7 and found that the embryonic arrest phenotype was the same as that for RNAi of cdk-7 alone. Expression of H01G02.2 in two budding yeast cak1 mutants, cak1-22 (Kaldis, Sutton, and Solomon 1996
) and civ1-4 (Thuret et al. 1996
), failed to rescue the lethal cak1 mutant phenotype (data not shown). In contrast, other researchers have expressed csk1 in the same mutants and found that it complemented cak1 (Hermand et al. 1998
). These results suggest that H01G02.2 is not likely to function as a CAK.
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Discussion |
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Four of the CDK clades contain members that have been shown to regulate transcription as CTD kinases of RNA Polymerase II. The KIN28 clade contains budding yeast Kin28 and human CDK7, both of which function as part of the general transcription factor TFIIH as CTD kinases to promote transcription (Orphanides, Lagrange, and Reinberg 1996
). Kin28 is required for the transcription of 87% of yeast genes (Holstege et al. 1998
). The SRB10 clade contains budding yeast Srb10 and human CDK8, both of which function as CTD kinases that negatively regulate transcription by phosphorylating the CTD of RNA Pol II prior to the assembly of the preinitiation complex (Hampsey and Reinberg 1999
). Srb10 negatively regulates 3% of yeast genes (Holstege et al. 1998
). The SGV1 clade contains H.s. CDK9 and D.m. Cdk9, both of which function as CTD kinases in pTEFb (positive transcription elongation factor b) to promote productive RNA Pol II elongation (Zhu et al. 1997
; Reines, Conaway, and Conaway 1999
). An sgv1 mutant has been found to suppress the effects of a deletion of an upstream activating sequence in yeast, suggesting a function in transcriptional regulation, but the exact mechanism of SGV1 action has not been determined (Prelich and Winston 1993
). The CTK1 clade contains budding yeast CTK1, which was isolated as an in vitro CTD kinase (Lee and Greenleaf 1991
). CTK1 was subsequently found to promote RNA Pol II elongation in vitro (Lee and Greenleaf 1997
) and to both activate and repress a subset of yeast genes in vivo (Patturajan et al. 1999
). It is interesting that of the seven ancestral CDK clades with both yeast and metazoan members, only the four CTD kinase-containing clades did not have an expansion in gene number from yeast to metazoa. In each of these clades, there is only a single ortholog in each species, with the exception of two closely related human genes in the CTK1 clade, CHED and KIAA0904.
The number of CDKs that regulate cell cycle progression has increased considerably from yeast to metazoa. In both budding and fission yeast, a single CDK, Cdc28 or Cdc2, respectively, is largely responsible for initiating all cell cycle progressions. In metazoans, H.s. CDK1/C.e. NCC-1/D.m. Cdc2 function in mitotic and meiotic progression; H.s. CDK4/H.s. CDK6/C.e. CDK-4/D.m. Cdk4 regulate G1 phase progression; and H.s. CDK2/D.m. Cdc2c function in S phase progression (King, Jackson, and Kirschner 1994
; Sherr 1994
; Stillman 1996
; Follette and O'Farrell 1997
; Boxem, Srinivasan, and van den Heuvel 1999
; Park and Krause 1999
). In contrast to this conservation of metazoan cell cycle CDKs, there is not a definitive ortholog of the S phase CDK, CDK2, in C. elegans. A potential C. elegans CDK2 counterpart is K03E5.3. While K03E5.3 branched at the base of the CDC28 and PHO85 clades (fig. 2
), distance matrices show that K03E5.3 is most similar to CDK2 and CDK3 (table 3
). It will be interesting to determine if K03E5.3 is required for DNA replication in C. elegans.
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The PHO85 clade has also undergone expansion in metazoans. There are three major metazoan subbranches, the CDK5 branch, the PFTAIRE branch, and the PCTAIRE branch (fig. 2
). There is a single orthologous gene in the CDK5 branch for all three metazoans. In vertebrates, CDK5 is expressed in postmitotic neuronal cells and is required for central nervous system and brain development (Ohshima et al. 1996
; Chae et al. 1997
). The PFTAIRE branch also has a single orthologous gene in all three metazoans. The function of the H.s. PFTK1 is unknown; its murine ortholog, PFTAIRE-1, is expressed in brain, testes, and embryos (Besset, Rhee, and Wolgemuth 1998
). There are three PCTAIRE subfamily members in humans and one in C. elegans, PCTAIRE1, 2, and 3 and pct-1, respectively. Noticeably absent is a D. melanogaster PCTAIRE family member. The three human PCTAIRE proteins have a high percentage of sequence identity among themselves (82%85%), suggesting a recent gene duplication. The functions of the human or C. elegans PCTAIRE genes are currently unknown.
The BC18H10.15 clade is unique as an ancestral clade that contains a fission yeast CDK family member, BC18H10.15, but no budding yeast counterpart. This presumably occurred due to the loss of the ancestral gene in budding yeast after the evolutionary divergence of yeast and metazoans. The BC18H10.15 clade contains two subbranches, PISSLRE and PITSLRE. The PISSLRE branch contains H.s. PISSLRE and D.m. Dcdrk. The PITSLRE branch contains two tandemly repeated human PITSLRE genes, two C. elegans genes, B0495.2 and ZC504.3, and D.m. Pitslre. The two expressed human PITSLRE genes, A and B, have only four amino acid differences in the kinase domain and are processed by alternative splicing into multiple isoforms (Lahti, Xiang, and Kidd 1995
). PITSLRE proteins are proteolytically processed during apoptosis to produce active truncated proteins (Lahti, Xiang, and Kidd 1995
). Expression of a truncated PITSLRE, similar to the proteolytically processed form, can induce apoptosis, and cells lacking PITSLRE have been found to be defective for apoptosis, suggesting that PITSLRE is an integral component of the apoptotic pathway (Lahti et al. 1995
; Ariza et al. 1999
). The functions of the ubiquitously expressed, nonproteolytically processed forms of PITSLRE are unknown. Inactivation of PISSLRE in mammalian cells with antisense and dominant-negative constructs produced a G2/M phase cell cycle arrest, suggesting a requirement of PISSLRE in this cell cycle transition (Li et al. 1995
).
The KKIALRE clade is an orphan clade that contains three human genes, KKIALRE, KKIAMRE, and STK9, one C. elegans gene, and one D. melanogaster gene. The cellular functions of none of these genes have been determined.
CAK1/csk1
Experimental data indicate that CAK1 and csk1 have analogous functions (Hermand et al. 1998
; Lee et al. 1999
). Our phylogenetic analysis indicates that they are orthologs. While the two taxa are very divergent, we believe that their branching together is indicative of a real orthologous relationship for three reasons. First, we observed significant CAK1-csk1 association with both the ML and the NJ methods, which are relatively resistant to the effects of long-branch attraction (Felsenstein 1978
; Saitou and Imanishi 1989
). Furthermore, we included a comprehensive data set of all available yeast, C. elegans, D. melanogaster, and human CDKs, as well as a variety of the closest outgroup taxa to minimize potential long-branch attraction effects (Lyons-Weiler and Hoelzer 1997
; Philippe and Laurent 1998
). Second, the CAK1/csk1 association remained after gamma rate correction of the data set to incorporate unequal rates of evolution at amino acid sites. Third, a reduced data set that no longer had a significant RASA Ftv (indicating the absence or diminution of a long-branch attraction problem) still had significant association of CAK1 and csk1.
The finding of orthologous CAK1/csk1 genes in both budding and fission yeast, which are distantly related to each other, suggests that an ortholog existed in the common ancestor of all eukaryotes, although it cannot be excluded that CAK1/csk1 arose in a fungal ancestor. In both NJ and ML analyses, the metazoan CDK family members D.m. AC014407 and C.e. H01G02.2 branched at the base of the CAK1 and csk1 node, while the human gene CCRK branched nearby. These associations were not well supported, with bootstrap values of between 17% and 27%. There is also no significant similarity between the primary sequence of these genes and CAK1 or csk1 (table 2 ; data not shown). Finally, there is no compelling evidence for orthology among the three metazoan genes themselves, which do not associate with high support values (fig. 2 ). Therefore, while it is possible that these genes arose from a CAK1/csk1 ancestor, sequence analysis cannot ascertain orthology. It is interesting that the primary sequence of C.e. H01G02.2 and H.s. CCRK indicates that they may be constitutively active. However, RNAi analysis suggests that C.e. H01G02.2 will not function as a CAK. It will be interesting to learn whether D.m. AC014407 or H.s. CCRK have CAK activity.
The absence of clearly identifiable CAK1/csk1 orthologs in metazoans lends support to a model for CAK function in metazoans originally proposed by Fisher et al. (1995)
(discussed below) and suggests a model for the evolution of CAK regulation in which the CAK1/csk1 gene was lost in metazoans. The model envisions an evolutionary progression from an ancestral state that was similar to the current situation in budding yeast, in which CAK1/csk1 provides the only CAK activity for all CDKs (fig. 4
). In a later ancestor, similar to fission yeast, the transcription CDK, Mcs6/CDK7, acquired the ability to function as a CAK and functions redundantly with Cak1/Csk1 to activate other CDKs. Although redundant for CAK activity, neither Cak1/Csk1 nor Mcs6/CDK7 is in danger of being eliminated, as Cak1/Csk1 is required to activate Mcs6/CDK7 and Mcs6/CDK7 is an essential transcription component. The final evolutionary progression is to a state similar to metazoans in which CAK1/csk1 has been eliminated. To allow this elimination, an alternate CAK for Mcs6/CDK7 is necessary. It has been observed that CDK2-Cyclin A and CDC2-Cyclin B can phosphorylate CDK7 in vitro (Fisher et al. 1995
; Martinez et al. 1997
) and therefore could activate CDK7 in vivo. However, this leaves a theoretical quandary, in that for CDK7 to become active, it must first activate its own CAK. A potential solution, proposed by Fisher et al. (1995)
, is that CDK7 can be activated by binding to the assembly factor MAT1 (Fisher et al. 1995
). MAT1 facilitates interaction between CDK7 and Cyclin H, and the trimeric complex is active without Thr170 phosphorylation. In higher eukaryotes, MAT1 is found in complex with CDK7 both within and outside of the TFIIH transcription complex (Fisher et al. 1995
). In contrast, in budding yeast, MAT1 is found solely within the transcription complex (Feaver et al. 1997
), indicating that it would not be available to activate Kin28. The model suggests that the ability of MAT1 to form a complex with Mcs6/CDK7 independently of the TFIIH complex made Cak1/Csk1 activity completely redundant and therefore allowed its loss during evolution. Much of this model remains untested; in particular, it is not known if (1) other CDKs function as CAKs for CDK7 in vivo, (2) the MAT1/CDK7/Cyclin H complex functions as a CAK in vivo, or (3) CDK7 is the CAK for all CDKs in metazoans.
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Acknowledgements |
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Footnotes |
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1 Keywords: cyclin dependent kinase
evolution
CDK activating kinase
long-branch attraction
CDK
CAK
2 Address for correspondence and reprints: Edward T. Kipreos, Department of Cellular Biology, University of Georgia, Athens, Georgia 30602. E-mail: ekipreos{at}cb.uga.edu
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