Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Genetics. 2021 Mar 3;217(1):1-12. doi: 10.1093/genetics/iyaa002.
Commitment to mitosis is regulated by cyclin-dependent kinase (CDK) activity. In the fission yeast Schizosaccharomyces pombe, the major B-type cyclin, Cdc13, is necessary and sufficient to drive mitotic entry. Furthermore, Cdc13 is also sufficient to drive S phase, demonstrating that a single cyclin can regulate alternating rounds of replication and mitosis, and providing the foundation of the quantitative model of CDK function. It has been assumed that Cig2, a B-type cyclin expressed only during S phase and incapable of driving mitosis in wild-type cells, was specialized for S-phase regulation. Here, we show that Cig2 is capable of driving mitosis. Cig2/CDK activity drives mitotic catastrophe-lethal mitosis in inviably small cells-in cells that lack CDK inhibition by tyrosine-phosphorylation. Moreover, Cig2/CDK can drive mitosis in the absence of Cdc13/CDK activity and constitutive expression of Cig2 can rescue loss of Cdc13 activity. These results demonstrate that in fission yeast, not only can the presumptive M-phase cyclin drive S phase, but the presumptive S-phase cyclin can drive M phase, further supporting the quantitative model of CDK function. Furthermore, these results provide an explanation, previously proposed on the basis of computational analyses, for the surprising observation that cells expressing a single-chain Cdc13-Cdc2 CDK do not require Y15 phosphorylation for viability. Their viability is due to the fact that in such cells, which lack Cig2/CDK complexes, Cdc13/CDK activity is unable to drive mitotic catastrophe.
有丝分裂的启动受到细胞周期蛋白依赖性激酶(CDK)活性的调控。在裂殖酵母 Schizosaccharomyces pombe 中,主要的 B 型细胞周期蛋白 Cdc13 是有丝分裂进入所必需且充分的。此外,Cdc13 也足以驱动 S 期,这表明单个细胞周期蛋白可以调节交替的复制和有丝分裂循环,为 CDK 功能的定量模型提供了基础。一直以来,人们认为只在 S 期表达且不能在野生型细胞中驱动有丝分裂的 B 型细胞周期蛋白 Cig2 是专门用于 S 期调控的。在这里,我们证明了 Cig2 有驱动有丝分裂的能力。Cig2/CDK 活性可驱动有丝分裂灾难——在缺乏酪氨酸磷酸化抑制 CDK 的情况下,不可存活的小细胞中的致死性有丝分裂。此外,在没有 Cdc13/CDK 活性的情况下,Cig2/CDK 也可以驱动有丝分裂,并且组成型表达 Cig2 可以挽救 Cdc13 活性的丧失。这些结果表明,在裂殖酵母中,不仅假定的 M 期细胞周期蛋白可以驱动 S 期,而且假定的 S 期细胞周期蛋白也可以驱动 M 期,这进一步支持了 CDK 功能的定量模型。此外,这些结果为以前基于计算分析提出的一个令人惊讶的观察结果提供了一个解释,即表达单链 Cdc13-Cdc2 CDK 的细胞不需要 Y15 磷酸化就能存活。它们的存活是因为在这些细胞中,缺乏 Cig2/CDK 复合物,Cdc13/CDK 活性无法驱动有丝分裂灾难。