Cyclin-dependent kinase 7

DEVELOPMENTAL BIOLOGY

Embryonic

A single 1.6-kb Drosophila Cdk7 poly(A+) RNA species is present throughout development and accumulates most strongly in ovaries and young embryos, where it is probably maternally deposited (Larochelle, 1998).

Characterization of a Drosophila ortholog of the Cdc7 kinase: A role for Cdc7 in endoreplication independent of Chiffon

Cdc7 is a serine-threonine kinase that phosphorylates components of the pre-Replication Complex during DNA replication initiation. Cdc7 is highly conserved, and Cdc7 orthologs have been characterized in organisms ranging from yeast to humans. Cdc7 is activated specifically during late G1/S phase by binding to its regulatory subunit, Dbf4. Drosophila melanogaster contains a Dbf4 ortholog, Chiffon, which is essential for chorion amplification in Drosophila egg chambers. However, no Drosophila ortholog of Cdc7 has been characterized as of yet. This paper reports the functional and biochemical characterization of a Drosophila ortholog of Cdc7. Co-expression of Drosophila Cdc7 and Chiffon is able to complement a growth defect in yeast containing a temperature-sensitive Cdc7 mutant. Cdc7 and Chiffon physically interact, and can be co-purified from insect cells. Cdc7 phosphorylates the known Cdc7 substrates Mcm2 and histone H3 in vitro, and Cdc7 kinase activity is stimulated by Chiffon and inhibited by the Cdc7-specific inhibitor XL413. Drosophila egg chamber follicle cells deficient for Cdc7 have a defect in two types of DNA replication, endoreplication and chorion gene amplification. However, follicle cells deficient for Chiffon have a defect in chorion gene amplification, but still undergo endocycling. These results show that Cdc7 interacts with Chiffon to form a functional Dbf4-Dependent Kinase (DDK) complex, and that Cdc7 is necessary for DNA replication in Drosophila egg chamber follicle cells. Additionally, it was shown that Chiffon is a member of an expanding subset of DNA replication initiation factors that are not strictly required for endoreplication in Drosophila (Stephenson, 2014).

Effects of mutation or deletion

The physiological role of Cdk7 during the course of Drosophila development has been examined. By expressing dominant-negative forms of the kinase, Cdk7 function was altered at given developmental stages. Expression of Cdk7 mutants severely delays the onset of zygotic transcription in the early embryo, but does not alter the timing of the first 13 embryonic nuclear cycles. These results implicate Cdk7 in the control of transcriptional machinery in vivo. While cell cycle regulation is not sensitive to these manipulations of Cdk7 activity, it suggests that a distinct pool of CAK activity that is unaffected by expression of the cdk7^DN mutants is present in these embryos (Leclerc, 2000).

In order to test their effect on the endogenous Cdk7 function, the mutant proteins were expressed in the larval wing imaginal disc, a sensitive tissue where alterations of both transcription and proliferation controls provoke easily scorable and non-lethal adult phenotypes. Indeed, when expressed in the wing disc using the MS1096 GAL4 driver, D137R and T170A cdk7 mutants induce malformations ranging from alteration of the vein pattern to severe wing blade reduction, depending on the transgene copy number and the strength of the UAS line used. In order to test whether these phenotypes are due to a specific alteration of Cdk7 function, attempts were made either to rescue them by co-expressing a wild-type allele of cdk7, or to enhance them by reducing the dosage of the endogenous cdk7 gene. The intermediate phenotypes obtained with two copies of weak cdk7 dominant constructs were enhanced in a cdk7^null#3 heterozygous background. Conversely, overexpression of a wild-type cdk7 allele does not produce a wing phenotype by itself, but rescues the phenotypes induced by expression of both cdk7 dominant alleles. It was concluded from these experiments that expression of the two dominant cdk7 alleles D137R and T170A specifically interfer with endogenous Cdk7 function (Leclerc, 2000).

High expression of the Cdk7^DN proteins in the anterior part of embryos repeatedly results in a defect in transcript accumulation of the fushi tarazu (ftz) gene, one of the earliest zygotic genes transcribed in the blastoderm embryo. Furthermore, at the end of the maternal division program, a corresponding zone with twice the normal density of interphase 14 nuclei is observed, resulting from the appearance of an extra synchronous division in the domain of expression of the Cdk7^DN proteins. In order to characterize this effect better, an early zygotic GAL4 driver (Krüppel-GAL4) was used, allowing a strong central expression of UAS constructs in the blastoderm embryo. When crossed with UAS-cdk7 D137R and T170A lines, a delay was observed in early zygotic transcription of the ftz gene occurring in the domain of expression of the Cdk7^DN proteins. The defect in ftz transcription is also accompanied by a delay in cellularization and an extra division of the blastoderm nuclei, supporting the idea of a general delay in the onset of zygotic transcription. It is known that termination of the maternal division program in Drosophila embryos is under the control of zygotic transcription, which induces an abrupt degradation of the maternal transcripts coding for the two Cdc25 mitotic inducers Twine and string. Blocking the onset of zygotic transcription generates an extra round of maternal division by stabilizing maternal twine and string messages. To confirm that the Cdk7^DN effect on the division program is a consequence of a stabilization of the maternal cdc25 transcripts, the maternal dose of the cdc25^twine gene was increased in an embryo expressing low levels of Cdk7^DN. Although neither one copy of the cdk7^DN transgene nor four copies of maternal cdc25^twine could induce extra divisions on their own, together they promot an extra mitosis in the Cdk7^DN expression domain. Thus, increasing gene dosage of cdc25^twine enhances the cdk7^DN effect. This indicates that the primary effect of Cdk7^DN is to delay zygotic transcription, therefore stabilizing maternal twine transcripts and preventing exit from syncytial divisions (Leclerc, 2000).

In an effort to correlate the timing of accumulation of Cdk7 with its function during early embryogenesis, an analysis of RNA and protein levels during the first period of development was performed. Cdk7 is maternally provided, although early embryos are only faintly labeled using a cdk7 antisense probe. Surprisingly, embryos at the time of pole cell formation (cycles 9-11) present a much stronger labeling, suggesting that zygotic transcription of the gene might be starting at that period. A weaker signal is present in older embryos. Protein level analysis on time-sorted embryos shows only a modest increase of the Cdk7 protein during early embryogenesis. Western blot analysis of polII indicates that the transcriptionally active, phosphorylated form of the CTD (IIo) is not present during the pre-blastoderm period and appears only after pole cell formation to accumulate progressively during later stages. Careful analysis of polII accumulation reveals that an intermediate phosphorylated form is present transiently during the pre-blastoderm period, which could correspond to the previously described polIIe in mammalian embryos. This phosphorylation intermediate disappears at the time of pole cell formation and is replaced by the typical IIo form, which involves Cdk7 kinase activity. Thus, it appears that although Cdk7 protein is present during early embryonic stages, its physiological target is not phosphorylated in vivo (Leclerc, 2000).

The phosphorylation state of Cdc2 during early embryonic cycles has been established. Starting from cell cycle 8, Cdc2 was dephosphorylated periodically on T161 during interphase, thus requiring a CAK activity to re-enter mitosis. In this context, the present data suggest two possible explanations. Different levels of activity could be required for the two possible functions of Cdk7 in vivo, suggesting transcription control requiring a higher level than cell cycle control. This would allow DN mutant expression to induce transcription defects in conditions where cell cycle control is not affected. Alternatively, a different pool of CAK activity distinct from Cdk7 complexes might be present to allow re-activation of the Cdc2 kinase prior to each mitosis in the absence of Cdk7 function. In S.cerevisiae, the TFIIH-associated CTD kinase and CAK activities are carried out by separate enzymes, Kin28/Ccl1/Tfb3 and Cak1, respectively. In S.pombe, both Cdk7 (or Mcs6) and Csk1, a monomeric kinase, are involved in CAK function in vivo. Analysis of a cdk7 null mutation in Drosophila had suggested that Cdk7 might be responsible only for Cdc2 phosphorylation and that another CAK activity could be responsible at least for the activation of Cdk2. Very recently a distinct CAK activity in human HepG2 cells has been described that does not fractionate with Cdk7 complexes; it reacts with anti-yeast Cak1 antibodies and could be the target of transforming growth factor-beta leading to G₁ arrest in these cells. A similar activity, distinct from the Cdk7 complex and reacting with antibodies against yeast Cak1, has recently been partially purified from HeLa cells. In Drosophila embryonic extracts, a 42 kDa protein species has been found that specifically cross-reacts with anti-yeast Cak1 antibodies. These studies and the present data strongly suggest that a distinct enzyme might be able to re-activate Cdc2 kinase periodically in the absence of Cdk7 during early embryonic cycles (Leclerc, 2000 and references therein).

Expression of the Cdk7^DN proteins induces a delay in early zygotic transcription, manifested by the absence of pair-ruled ftz gene transcription, a delay in cellularization and a failure to terminate syncytial divisions following interphase 13. Several lines of evidence have shown that a defect in early transcription in embryos is associated with a failure to undergo cellularization and to end the program of maternal divisions. These two events are the hallmark of mid-blastula transition because they are the earliest developmental events in the embryo known to require zygotic transcription. Blastoderm cellularization is under the control of a number of zygotic genes (bottleneck, serendipity-alpha and nullo), whose expression is required early in interphase 14. The termination of blastoderm mitoses depends on the degradation of maternal cdc25^twine and cdc25^string transcripts. Recent work has pointed to two different pathways leading to the degradation of maternal mRNAs. One is maternally encoded and responsible for a progressive disappearance of maternal transcripts. The second is zygotically activated 2 h after fertilization and results in a more abrupt RNA degradation. The function of both pathways is necessary for the complete elimination of transcripts at mid-blastula transition. Indeed, embryos injected with alpha-amanitin do not cellularize and display a delay in degradation of both maternal cdc25 RNAs, resulting in a 14th synchronous syncytial nuclear division. The experiments described here confirm that the Cdk7^DN effect on the program of syncytial divisions is a consequence of a transcriptional effect on mRNA degradation, since increasing the cdc25^twine maternal dosage results in a strong enhancement of the cdk7^DN phenotype (Leclerc, 2000 and references therein).

Despite the effects of cdk7^DN expression on the transcription program, no consistent variations of the phosphorylation levels of polII CTD, one of the known targets of the TFIIH kinase, were observed. This is probably due to the fact that the expression system used was too localized to induce a general decrease of polII phosphorylation levels that could be detected. Additionally, during this early period, polII phosphorylation evolves rapidly, which makes the staging of the embryos used for analysis particularly crucial (Leclerc, 2000).

Taken together, these experiments implicate Cdk7 function in the onset of transcription at mid-blastula transition and constitute the first in vivo evidence that Cdk7 function is essential for the regulation of the transcriptional machinery in higher eukaryotes. Interestingly, two recent reports suggest that TFIIH could be the target of a mechanism of transcriptional repression during mitosis. In these studies, it was demonstrated that upon entry into mitosis, TFIIH is phosphorylated on its p36 (Cdk7) subunit and that this phosphorylation results in inhibition of the Cdk7-associated CTD kinase and, consequently, of the transcriptional activity of the TFIIH complex. Furthermore, this inhibitory phosphorylation can be carried out in vitro by mitotic kinase Cdc2-cyclin B, suggesting that there might be a direct interaction between Cdc2 and Cdk7 that leads to inhibition of the CTD kinase activity of Cdk7. Mitotic inhibition of transcription can be related through many points to pre-blastoderm inhibition of transcription. In early embryos, it has been shown that the mitotic kinase Cdc2 is constitutively active through the first nuclear cycles, until cell cycle 9, when inactivation of Cdc2 can be detected first in interphase. This coincides precisely with the moment when earliest traces of transcription can be detected using ftz probes. Inhibition of transcription by the Cdc2 kinase is one of the mechanisms that has been proposed for delaying the onset of zygotic transcription. More recently, analysis of the grapes and mei-41 mutations in flies has shown that the progressive lengthening of interphases 11, 12 and 13 is also essential for proper accumulation of zygotic transcripts, but suggests that additional mechanisms repress transcription during blastoderm cycles. It is proposed that, as in mitotic cells, the transcription machinery in the pre-blastoderm embryo could be inhibited by a specific mechanism involving the mitotic kinase Cdc2, with Cdk7 as one of its possible targets. These results reinforce this hypothesis, since no polIIo (phosphorylated form of the CTD domain) is found accumulating at pre-blastoderm stages, suggesting a possible early inhibition of the in vivo CTD kinase activity of Cdk7. The presence of a modified IIe-like form of polII in pre-blastoderm embryos was also noticed. Alternatively, absence of CTD phosphorylation by Cdk7 at this stage could be explained by a transient cytosolic localization of polII, as has been described for the IIe form in rabbit embryos. Although mostly speculative, these models should serve as a framework for further analyses of the regulation of polII machinery during early embryogenesis (Leclerc, 2000).

Lack of zygotically expressed cdk7 results in death before or soon after the initiation of pupation. cdk7^null animals often remain in a larval state, noticeably longer that their cdk7⁺ siblings; under optimal conditions, up to 50% of the mutant larvae form a puparium, and the remainder die as larvae. cdk7^null larvae exhibit defects consistent with a disruption of mitotic activity. In cdk7^null animals, the imaginal discs fail to proliferate and do not reach their normal size, whereas the polyploid tissue, which proceeds through replicative S-phases without mitosis, appears normal. This phenotype resembles the one seen in loss-of-function cdc2 mutants (Drosophila Cdc2 is a cyclin dependent kinase and is the dimerization partner of Cyclin A, Cyclin B and Cyclin B2) (Larochelle, 1998).

To be able to study the requirements for cdk7 activity in different tissues and at different times during development, a temperature-sensitive allele was created. Temperature-sensitive mutations in the related cdc2 and Mek suggest that substituting the conserved proline residue 140 for a serine is likely to confer temperature sensitivity on cdk7. Therefore, this mutation was introduced into cdk7 by site-directed mutagenesis, and the modified gene was reintroduced into flies. Animals carrying a cdk7⁺ transgene in the cdk7^null background are 100% viable at all temperatures tested, whereas those carrying the cdk7^P140S allele in the null background prove to be fully viable at 18°C but not viable at 27°C or above. These results demonstrate that the P140S mutation results in a temperature-dependent inactivation of cdk7. Flies carrying only the cdk7^P140S transgene as a source of Cdk7 protein will therefore be referred to as cdk7^ts mutants. After transfer of mutant mothers to the restrictive temperature, many of the embryos laid during the first 36 hr eclose as larvae. Most of the embryos that fail to eclose during this period exhibit defects late in development. Mutant embryos exhibit gradually earlier developmental arrest to a point where the embryonic nuclear division program fails to be initiated (Larochelle, 1998).

When immunoprecipitated Cdk7^P140S is used in CAK assays, a significant amount of activity is still present in embryos from females kept at the restrictive temperature for 1 day. Some activity can still be detected after 2 days at the restrictive temperature. Similarly, the Cdk7^P140S protein fails to be inactivated rapidly in vivo by incubation at high temperature. What then is the basis of the temperature sensitivity of cdk7^ts? Embryos and ovaries isolated from Cdk7^ts animals kept at the restrictive temperature show a progressive reduction of Cdk7 protein levels with time. The data suggest that the P140S mutation interferes with the stability of the mutant protein synthesized at the restrictive temperature, whereas the mutant protein synthesized at the permissive temperature retains significant activity until turned over. The described properties of the P140S mutation can explain the existence of a lag phase between the shift of temperature-sensitive mothers to the restrictive temperature and the appearance of the mutant phenotype in embryos. Like their cdk7⁺ siblings, mutant adults allowed to develop at the permissive temperature can live for >40 days after transfer to the restrictive temperature. The production of gametes, however, stops in cdk7^ts animals as females transferred to the restrictive temperature cease to lay eggs after 3-4 days as a result of compromised cell division in the germ line and supporting somatic tissue (Larochelle, 1998).

In Drosophila, the ovary consists of a number of tube-like structures called ovarioles; at the tips, two to three mitotically active germ-line stem cells continuously divide. The asymmetric division of a stem cell gives rise to another stem cell and a cystoblast that then goes through four incomplete mitotic divisions, resulting in a cyst of 16 germ cells connected to one another by cytoplasmic bridges. As the 16-cell cyst moves posteriorly down the ovariole, it becomes enveloped by a continuous monolayer of somatic follicle cells that are also supplied by dividing stem cells. When pupae are transferred to the restrictive temperature, viable cdk7^ts mutant adults continue to eclose for up to 3 days after the temperature shift to 29°C. These animals exhibit normal adult viability when kept at the restrictive temperature, but the mitotically active tissues exhibit progressively stronger defects with increasing time spent at 29°C. When females eclose shortly after transfer to 29°C, the first abnormality observed in cdk7^ts ovaries is the depletion of the somatic follicle cells. A rapid depletion of follicle cells is predicted to occur if cell division is compromised, since each daughter of the follicle stem cells must divide approximately nine times to produce the 1200 follicle cells surrounding each germ-line cyst. The depletion of follicle cells in the cdk7^ts mutant shows that cdk7 is required for the mitotic division of these somatically derived cells. After the reduction in the number of follicle cells surrounding each egg chamber, the effect on the mitotic activity of the germ line becomes apparent when cysts are found that possess fewer than the normal number of 16 germ cells (Larochelle, 1998).

Cyclin E was shown previously to function during endoreplication of polyploid tissues, and its activity is thought to be mediated through the activation of Cdk2. Therefore, it was surprising that although cell proliferation is arrested completely in cdk7^ts ovaries, the capability of these cells to endoreplicate their DNA is not affected. Two explanations could account for the lack of effect on endoreplication: (1) Cdk2 is not involved in DNA synthesis during endoreplication. This possibility cannot be excluded formally as no mutant phenotype has been described so far for cdk2. (2) Cdk2 may not require threonine phosphorylation for its DNA synthesis-promoting activity during endoreplication (Larochelle, 1998).

Because Cdk7 has also been implicated in the phosphorylation of the C-terminal domain (CTD) of RNA Pol II as part of the TFIIH complex, the cell cycle arrest observed in the cdk7 mutants could be an indirect result of reduced RNA Pol II activity, which in turn would result in low cyclin levels. To determine whether reduced cdk7 activity results in a decrease in cyclin levels, the amount of the different cyclins present in the mutant and wild-type embryos was determined by immunoblot. The level of all three cyclins is high in embryos from cdk7^ts parents during stages when they are also present at high levels in wild-type embryos. These observations indicate that the lack of cdk7 does not cause a noticeable reduction in cyclin levels. Cyclins A and B are expressed uniquely in mitotically active cells. In total lysates from embryos at different stages of development, the level of mitotic cyclin proteins is greatly reduced in later development. The high level of Cyclins A and B still observed in cdk7^ts embryos aged >6 hr is attributable to the fact that these embryos arrested development at a stage when mitotic cyclin levels are still high. Another observation suggesting that transcription in general is not disrupted is the fact the germ-line cells can still endoreplicate their DNA in mutant cdk7^ts ovaries. Endoreplication has been proposed to require the pulse transcription of cyclin E in embryonic tissues, and presumably also in the ovary (Larochelle and references, 1998).

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