Abstract
Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells to do so. Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell size homeostasis.
Highlights
Cells display homeostatic behaviour in maintaining population cell size by controlling cell size at mitosis (Fantes et al, 1975; Ginzberg et al, 2015; Wood and Nurse, 2015; Lloyd, 2013)
CDK activity is subject to several mechanisms of control: cyclin synthesis and subsequent binding of cyclin to CDK, which drives CDK into a catalytically competent form Solomon et al, 1990; Wee1 kinase and Cdc25 phosphatase act to inhibit or activate CDK, respectively, through regulatory tyrosine phosphorylation (Nurse, 1975; Russell and Nurse, 1986; Gould and Nurse, 1989); and PP2A phosphatase works to remove phosphates deposited by CDK reducing its net activity (Kinoshita et al, 1990; Kinoshita et al, 1993; Gharbi-Ayachi et al, 2010; Mochida et al, 2009; Mochida et al, 2010; Mochida et al, 2016), and controls the phosphorylation state of Wee1 and Cdc25 to regulate the level of CDK tyrosine phosphorylation (Lucena et al, 2017; Hutter et al, 2017; Rata et al, 2018; Kamenz et al, 2021)
A number of regulatory components have been shown to be conserved across these model systems, including the CDK-activating cyclin B, inhibitory CDK tyrosine phosphorylation, and the CDK-counteracting PP2A phosphatase which both opposes CDK substrate phosphorylation and regulates CDK inhibitory phosphorylation through the Wee1/Cdc25 control loop
Summary
Cells display homeostatic behaviour in maintaining population cell size by controlling cell size at mitosis (Fantes et al, 1975; Ginzberg et al, 2015; Wood and Nurse, 2015; Lloyd, 2013). This homeostasis is driven by larger cells being more likely to divide than smaller cells, resulting in the correction at cell division of cell size deviances (Fantes et al, 1975; Fantes, 1977; Patterson et al, 2019).
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