Candida albicans Cyclin Clb4 Carries S-Phase Cyclin Activity

Abstract

Cyclin-dependent kinases (CDKs) are key regulators of eukaryotic cell cycle progression. The cyclin subunit activates the CDK and also imparts to the complex, at least in some cases, substrate specificity. Saccharomyces cerevisiae, an organism in which the roles of individual cyclins are best studied, contains nine cyclins (three G 1 cyclins and six B-type cyclins) capable of activating the main cell cycle CDK, Cdc28. Analysis of the genome of the pathogenic yeast Candida albicans revealed only two sequences corresponding to B-type cyclins, C. albicans Clb2 (CaClb2) and CaClb4. Notably, no homolog of the S. cerevisiae S-phase-specific cyclins, Clb5/ Clb6, could be detected. Here, we performed an in vitro analysis of the activity of CaClb2 and CaClb4 and of three G 1 cyclins, as well as an analysis of the phenotype of S. cerevisiae cells expressing CaClb2 or CaClb4 instead of Clb5. Remarkably, replacement of CLB5 by CaCLB4 caused rapid diploidization of S. cerevisiae. In addition, both in vivo and in vitro analyses indicate that, in spite of the higher sequence similarity of CaClb2 to Clb5/Clb6, CaClb4 is the functional homolog of Clb5/Clb6. The activity of a CaClb2/CaClb4 cyclin hybrid suggests that the cyclin box domain of CaClb4 carries the functional specificity of the protein. These results have implications for our understanding of the evolution of specificity of the cell cycle cyclins.Cyclin-dependent kinases (CDKs) regulate many cellular processes but are best known for their role in the promotion of cell cycle progression. CDK activity depends on the binding of activatory subunits, the cyclins, which periodically appear during the cell cycle. Saccharomyces cerevisiae contains a single essential cell cycle CDK, S. cerevisiae Cdc28 (ScCdc28)/Cdk1, which in turn can be activated by nine cyclins: three G 1 -type cyclins (Cln1, Cln2, and Cln3) and six B-type cyclins (S. cerevisiae Clb1 [ScCbl1] to ScCbl6) (34). Cln3 together with Cln1 and Cln2 (Cln1/2) induces a large class of cell cycle-regulated genes, including genes involved in S-phase initiation, such as the B-cyclins Clb5 and Clb6 (Clb5/6) (44, 47). Clb3 and Clb4 are expressed from early S phase to anaphase (22) and play a role in spindle orientation (Clb4) (31) and morphogenesis (Clb3 and Clb4) (25,37), and Clb1 and Clb2 are expressed in G 2 (22) and play a role in entry into anaphase and spindle elongation (18). Genetic analysis suggests that the genes CLB1 to CLB4 have overlapping functions, as deletions of all four is lethal, but a mutant with deletion of all but CLB2 is still viable (18). Deletion of both CLB5 and CLB6 or of CLB5 alone is not lethal but results in a delay in S-phase initiation (41).The diverged yeast Schizosaccharomyces pombe contains one G 1 cyclin and three B-type cyclins. Studies indicating that a single S. pombe B-type cyclin,

The Hog1 MAP Kinase Promotes the Recovery from Cell Cycle Arrest Induced by Hydrogen Peroxide in Candida albicans

“…Sol1 was identified as functional homolog of S. cerevisiae Sic1 in C. albicans . In C. albicans Sol1 may play a similar role to Sic1, as it has been reported that Sol1 inhibits CaClb4 and CaClb2 and that CaSol1 at high concentration is itself a substrate of both CaClb2 and CaClb4 (Ofir and Kornitzer, 2010). We show that Sol1 accumulates in the presence of oxidative challenge.…”

CDK Regulates Septin organization through Cell-cycle-dependent Phosphorylation of the Nim1-related Kinase Gin4

“…However, the association of Gin4 with Clb2 was markedly stronger than with Clb4. This might be explained by the recent finding that Clb2 is the mitotic cyclin in C. albicans (Ofir and Kornitzer, 2010). By contrast, Gin4 association was barely detectable with either one of the two G1 cyclins Ccn1 and Cln3 (Fig.…”

Role of a Candida albicans Nrm1/Whi5 homologue in cell cycle gene expression and DNA replication stress response

“…Alternatively, no such homologue exists and C. albicans ensures the irreversibility of START by other means. Supporting the latter possibility is that no sequence homologues of the Cln1/2 cyclins can be detected in C. albicans besides Hgc1, which is not known to play a role in cell cycle progression (Zheng and Wang, 2004; Ofir and Kornitzer, 2010).…”

“…Schematic depiction of CaNrm1 localization and CaNrm1-CaSwi4/CaSwi6 interaction during the cell cycle and after exposure to hydroxyurea. detected in C. albicans besides Hgc1, which is not known to play a role in cell cycle progression (Zheng and Wang, 2004;Ofir and Kornitzer, 2010).…”