Abstract
CDKs (cyclin-dependent kinases) associate with different cyclins to form different CDK-complexes that are fundamental for an ordered cell cycle progression, and the coordination of this progression with different aspects of the cellular physiology. During meiosis programmed DNA double-strand breaks (DSBs) initiate recombination that in addition to generating genetic variability are essential for the reductional chromosome segregation during the first meiotic division, and therefore for genome stability and viability of the gametes. However, how meiotic progression and DSB formation are coordinated, and the role CDKs have in the process, is not well understood. We have used single and double cyclin deletion mutants, and chemical inhibition of global CDK activity using the cdc2-asM17 allele, to address the requirement of CDK activity for DSB formation and recombination in fission yeast. We report that several cyclins (Cig1, Cig2, and the meiosis-specific Crs1) control DSB formation and recombination, with a major contribution of Crs1. Moreover, complementation analysis indicates specificity at least for this cyclin, suggesting that different CDK complexes might act in different pathways to promote recombination. Down-regulation of CDK activity impinges on the formation of linear elements (LinEs, protein complexes required for break formation at most DSB hotspot sites). This defect correlates with a reduction in the capability of one structural component (Rec25) to bind chromatin, suggesting a molecular mechanism by which CDK controls break formation. However, reduction in DSB formation in cyclin deletion mutants does not always correspondingly correlate with a proportional reduction in meiotic recombination (crossovers), suggesting that specific CDK complexes might also control downstream events balancing repair pathways. Therefore, our work points to CDK regulation of DSB formation as a key conserved feature in the initiation of meiotic recombination, in addition to provide a view of possible roles CDK might have in other steps of the recombination process.
Highlights
Eukaryotic cell cycle progression is driven by sequentially organized accumulation of different CDK activities formed by a catalytic serine/threonine kinase that binds to a regulatory cyclin subunit [1,2,3]
Cig1 and Cig2 cyclins are expressed around S-phase and prophase, and Cig2 required for meiotic DNA replication [63, 64]
It is not well established that control of double-strand breaks (DSBs) formation by CDK activity is a universal feature of meiosis
Summary
Eukaryotic cell cycle progression is driven by sequentially organized accumulation of different CDK (cyclin-dependent kinase) activities formed by a catalytic serine/threonine kinase that binds to a regulatory cyclin subunit [1,2,3]. In Schizosaccharomyces pombe a single CDK (Cdc2) and six different cyclins have been described. Though at least in this yeast a single CDK complex (Cdc kinase-Cdc cyclin) can promote both mitotic and meiotic progression, it is not as efficient as in the wild-type situation where additional CDK complexes are present [8, 9]. This indicates that distinct cyclins have evolved to optimize different aspects of the mitotic and the meiotic divisions and that some kind of specificity is provided by each CDK complex (Cdc2-Cyclin). Two of the described cyclins (Rem and Crs1) are meiosis-specific [10, 11], suggesting meiosis-specific functions for these CDKcomplexes
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