Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States of America.
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS Genet. 2022 Aug 29;18(8):e1010349. doi: 10.1371/journal.pgen.1010349. eCollection 2022 Aug.
A network of transcription factors (TFs) coordinates transcription with cell cycle events in eukaryotes. Most TFs in the network are phosphorylated by cyclin-dependent kinase (CDK), which limits their activities during the cell cycle. Here, we investigate the physiological consequences of disrupting CDK regulation of the paralogous repressors Yhp1 and Yox1 in yeast. Blocking Yhp1/Yox1 phosphorylation increases their levels and decreases expression of essential cell cycle regulatory genes which, unexpectedly, increases cellular fitness in optimal growth conditions. Using synthetic genetic interaction screens, we find that Yhp1/Yox1 mutations improve the fitness of mutants with mitotic defects, including condensin mutants. Blocking Yhp1/Yox1 phosphorylation simultaneously accelerates the G1/S transition and delays mitotic exit, without decreasing proliferation rate. This mitotic delay partially reverses the chromosome segregation defect of condensin mutants, potentially explaining their increased fitness when combined with Yhp1/Yox1 phosphomutants. These findings reveal how altering expression of cell cycle genes leads to a redistribution of cell cycle timing and confers a fitness advantage to cells.
转录因子（TFs）网络在真核生物中协调转录与细胞周期事件。该网络中的大多数 TF 都被细胞周期依赖性激酶（CDK）磷酸化，这限制了它们在细胞周期中的活性。在这里，我们研究了破坏酵母中同源抑制因子 Yhp1 和 Yox1 的 CDK 调节对生理的影响。阻止 Yhp1/Yox1 的磷酸化会增加它们的水平，并降低必需的细胞周期调控基因的表达，这出人意料地增加了细胞在最佳生长条件下的适应性。通过合成遗传相互作用筛选，我们发现 Yhp1/Yox1 突变可改善有丝分裂缺陷突变体（包括凝聚酶突变体）的适应性。阻止 Yhp1/Yox1 的磷酸化可同时加速 G1/S 转换并延迟有丝分裂退出，而不会降低增殖速度。这种有丝分裂延迟部分逆转了凝聚酶突变体的染色体分离缺陷，这可能解释了它们与 Yhp1/Yox1 磷酸突变体组合时适应性增加的原因。这些发现揭示了如何改变细胞周期基因的表达导致细胞周期时间的重新分配，并赋予细胞适应性优势。
