Human Cdk2 is a functional homolog of budding yeast Ime2, the meiosis-specific Cdk-like kinase

Abstract

Progression through the cell cycle depends on sequential activation of Cyclin-Dependent Kinase(s). In this report we use budding-yeast meiosis as a tool to elucidate the specific functions of mammalian Cdks. Yeast meiosis is regulated by both Cdc28 (yCdk1) and Ime2 (a meiosis-specific Cdk-like kinase). We show that human Cdk2 is a functional homolog for most of Ime2 functions. It promotes efficient and timely entry into premeiotic DNA replication and the first nuclear division, as well as the regulated transcription of IME1 and the early meiosis-specific genes. We show that this effect is specific, and that neither mice Cdk1, nor mice Cdk4 can suppress ime2. We show that Cdk1 is a functional homolog of Cdc28 that also suppresses one of its meiotic functions, namely inhibiting the transcription of IME1. Cdk2, on the other hand, show dominant negative effects on entry into the cell cycle, most probably by inhibiting the function of Cdc28. Finally, we show that in the meiotic pathway Cdk4 functions as a transcriptional activator.

Understanding meiosis and the implications for crop improvement

“…Transcript analysis of TaASY1 in ph1b showed a significant 20-fold increase relative to wild-type. Interestingly, this observation is consistent with recent observations of HOP1 gene activity in yeast meiosis following deletion of the Cdk2 homologue, named Inducer of meiosis 2 (Ime2) (Szwarcwort-Cohen et al 2009), indicating the mechanism controlling chromosome pairing is conserved across eukaryotes. Additional evidence for TaASY1 being involved in bread wheat chromosome pairing was shown by Boden et al (2009) with the localisation patterns in the ph1b mutant being disrupted and spiral-like in appearance.…”

Ectopic expression of human Cdk2 and its yeast homolog, Ime2, is deleterious toSaccharomyces cerevisiae

“…Cdk/Cyclins could affect tumor formation through inducing an unregulated cell entry (as Cdk4 inhibition results in a G 1 arrest of colon cancer cells 19 ) and/or through a genotoxic effect (as constitutive overexpression of cyclin E in cancer cell lines results in chromosome instability 21 ). In the budding yeast Saccharomyces cerevisiae, Cdc28 and Ime2 are functional homologs of Cdk2, [22][23][24][25][26] as hCdk2 complements cdc28 mutations, and ectopic expression of hCdk2 (but not mCdk1 or mCdk4) suppressed some of the phenotypes observed in IME2-deleted cells. 26 Yeast cells carry a single Cdk, Cdc28, that in a complex with three G 1 cyclins (Cln1-3) and six B-type cyclins (Clb1-6) it regulates cell cycle entry and progression.…”

“…In the budding yeast Saccharomyces cerevisiae, Cdc28 and Ime2 are functional homologs of Cdk2, [22][23][24][25][26] as hCdk2 complements cdc28 mutations, and ectopic expression of hCdk2 (but not mCdk1 or mCdk4) suppressed some of the phenotypes observed in IME2-deleted cells. 26 Yeast cells carry a single Cdk, Cdc28, that in a complex with three G 1 cyclins (Cln1-3) and six B-type cyclins (Clb1-6) it regulates cell cycle entry and progression. 27 IME2 encodes a meiosis-specific CDK like kinase which is required for timely entry of cells into premeiotic DNA replication/nuclear division, high level transcription of the early meiosis-specific genes, transcription of the middle-and late meiosis-specific genes and spore formation.…”

“…Overexpression of either Ime2 or hCdk2 under vegetative growth conditions resulted in transcription of the early meiosis-specific gene HOP1. 26 Since some of the early meiosis-specific genes encode proteins that induce double-strand breaks (DSB), we postulated that toxicity may result from two reasons, an increase in DSB formation, and inhibition of Cdk1 Figure 2. overexpression of either Ime2 or hCdk2 delays entry into S phase.…”

A nutrient dependant switch explains mutually exclusive existence of meiosis and mitosis initiation in budding yeast

“…In one of the negative feedback loops between Ime2 and Cdk1/Cln3, functionality of Cdk1 is inhibited by Ime2, because probably all known substrates of Cdk1 are phosphorylated by Ime2 inhibiting the cell cycle progression (Holt et al, 2007;Szwarcwort-Cohen et al, 2009). …”