cdk-7 is required for mRNA transcription and cell cycle progression in Caenorhabditis elegans embryos

Abstract

CDK7 is a cyclin-dependent kinase proposed to function in two essential cellular processes: transcription and cell cycle regulation. CDK7 is the kinase subunit of the general transcription factor TFIIH that phosphorylates the C-terminal domain (CTD) of RNA polymerase II, and has been shown to be broadly required for transcription in Saccharomyces cerevisiae. CDK7 can also phosphorylate CDKs that promote cell cycle progression, and has been shown to function as a CDK-activating kinase (CAK) in Schizosaccharomyces pombe and Drosophila melanogaster. That CDK7 performs both functions in metazoans has been difficult to prove because transcription is essential for cell cycle progression in most cells. We have isolated a temperature-sensitive mutation in Caenorhabditis elegans cdk-7 and have used it to analyze the role of cdk-7 in embryonic blastomeres, where cell cycle progression is independent of transcription. Partial loss of cdk-7 activity leads to a general decrease in CTD phosphorylation and embryonic transcription, and severe loss of cdk-7 activity blocks all cell divisions. Our results support a dual role for metazoan CDK7 as a broadly required CTD kinase, and as a CAK essential for cell cycle progression.

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“…6 Some CDKs (CDK2, 4, 6) have a role in cell-cycle regulation by regulating the transition between G1/S phase, S-phase progression and G2/M transition. 7,8 In combination with extracellular signals and checkpoint pathways CDKs enforce tight regulation of the cell cycle.…”

The Plant-Specific Kinase CDKF;1 Is Involved in Activating Phosphorylation of Cyclin-Dependent Kinase-Activating Kinases in Arabidopsis

“…Recent reports indicate that Cak1p phosphorylates the T-loop of Kin28p and thereby stimulates its CTD-kinase activity (Kimmelman et al, 1999). This suggests that, despite their low sequence similarity, budding yeast Cak1p and fission yeast Csk1 perform similar functions by phosphorylating the CTD kinases, Kin28p and Mcs6. One of the best characterized animal CAKs, CDK7/p40 MO15 , occurs in complex with cyclin H and phosphorylates both CDK and the CTD of RNA polymerase II (Kaldis, 1999;Wallenfang and Seydoux, 2002). CDK7 and cyclin H are close homologs of Mcs6 and Mcs2, respectively (Damagnez et al, 1995).…”

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“…Temperature sensitive CDK7 mutants in C. elegans exhibit a block in the cell cycle which can be attributed to loss of CAK activity rather than any CTD phosphorylating function [30]; and in Drosophila CDK7 mutations are lethal and cause death before or during pupation due to mitotic catastrophe, similar to mutations in the CDK1 gene suggesting that the gene is required for mitotic proliferation [31]. Similarly in mice deletion of the MAT1 causes embryonic lethality.…”