Repression of essential cell cycle genes increases cellular fitness.
Repression of essential cell cycle genes increases cellular fitness.
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必需细胞周期基因的抑制会增加细胞适应性。
DOI：
10.1371/journal.pgen.1010349
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发表时间：
2022-08
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
在真核生物中，转录因子（TFs）网络与细胞周期事件协调转录。网络中的大多数tf被细胞周期蛋白依赖性激酶（CDK）磷酸化，这限制了它们在细胞周期中的活性。在这里，我们研究了在酵母中破坏CDK对副同源抑制因子Yhp1和Yox1的调节的生理后果。阻断Yhp1/Yox1磷酸化会增加它们的水平，并降低必要的细胞周期调节基因的表达，这出乎意料地增加了细胞在最佳生长条件下的适应性。通过合成基因相互作用筛选，我们发现Yhp1/Yox1突变提高了有丝分裂缺陷突变体的适应度，包括凝缩蛋白突变体。阻断Yhp1/Yox1磷酸化同时加速G1/S转变并延迟有丝分裂退出，但不降低增殖率。这种有丝分裂延迟部分逆转了凝聚蛋白突变体的染色体分离缺陷，这可能解释了它们与Yhp1/Yox1磷突变体结合时适应性增加的原因。这些发现揭示了细胞周期基因表达的改变如何导致细胞周期时间的重新分配，并赋予细胞适应性优势。对细胞分裂周期的适当调节对于防止可能导致癌症发展的不受控制的增殖至关重要。虽然有许多蛋白质控制这一过程，但突变有时会对细胞增殖产生意想不到的影响。在这里，我们研究了控制酵母细胞周期的两个部分冗余转录抑制因子的突变。增加这些抑制因子表达的突变导致必需细胞周期基因的表达减少，令人惊讶的是，细胞适应性增加。我们发现，通过调节细胞周期基因的表达，这些tf控制细胞在每个细胞周期阶段花费的时间。我们的研究结果表明，突变细胞在不降低增殖速率的情况下增加了有丝分裂的长度，因此突变细胞有更多的时间来纠正染色体分离错误。我们的研究结果表明，损害细胞周期特定阶段进展的突变如何赋予细胞适应性优势。
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. Proper regulation of the cell division cycle is essential to prevent uncontrolled proliferation that can lead to the development of cancer. Although numerous proteins have been characterized that control this process, mutations can sometimes have unexpected effects on cell proliferation. Here, we investigate mutations in two partially-redundant transcriptional repressors that control the cell cycle in yeast. Mutations that increase expression of these repressors result in decreased expression of essential cell cycle genes and, surprisingly, increase cellular fitness. We find that by regulating the expression of cell cycle genes these TFs control the amount of time cells spend in each cell cycle phase. Our results show that mutant cells increase the length of mitosis without decreasing proliferation rate, and as a result, mutant cells have more time to correct errors in chromosome segregation. Our findings demonstrate how mutations that impair progression of specific phases of the cell cycle can confer a fitness advantage to cells.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
14.9
作者：
Fischer M;Grossmann P;Padi M;DeCaprio JA
通讯作者：
DeCaprio JA
影响因子：
3.3
作者：
Lavoie, BD;Tuffo, KM;Holm, C
通讯作者：
Holm, C
影响因子：
9.3
作者：
Baryshnikova, Anastasia
通讯作者：
Baryshnikova, Anastasia
DOI：
10.1083/jcb.149.4.811
发表时间：
2000-05-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Freeman L;Aragon-Alcaide L;Strunnikov A
通讯作者：
Strunnikov A