Restriction of DNA Replication to the Reductive Phase of the Metabolic Cycle Protects Genome Integrity

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Science (Impact Factor: 33.61). 07/2007; 316(5833):1916-9. DOI: 10.1126/science.1140958
Source: PubMed


When prototrophic yeast cells are cultured under nutrient-limited conditions that mimic growth in the wild, rather than in the high-glucose solutions used in most laboratory studies, they exhibit a robustly periodic metabolic cycle. Over a cycle of 4 to 5 hours, yeast cells rhythmically alternate between glycolysis and respiration. The cell division cycle is tightly constrained to the reductive phase of this yeast metabolic cycle, with DNA replication taking place only during the glycolytic phase. We show that cell cycle mutants impeded in metabolic cycle-directed restriction of cell division exhibit substantial increases in spontaneous mutation rate. In addition, disruption of the gene encoding a DNA checkpoint kinase that couples the cell division cycle to the circadian cycle abolishes synchrony of the metabolic and cell cycles. Thus, circadian, metabolic, and cell division cycles may be coordinated similarly as an evolutionarily conserved means of preserving genome integrity.

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Available from: Zheng Chen, Dec 10, 2014
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    • "For example, the condensed form with high OXPHOS capacity could be termed as 'oxidative state' with more ROS generation, and the orthodox form with low respiration capacity as 'reductive state' with less ROS generation while the intermediate form could be a 'neutral state'. As mitochondrion is the major source of endogenous ROS with potential genomic toxicity , reductive state created by glycolysis without ROS (the Warburg effect) and its synchronization with DNA replication could be vital to prevent spontaneous mutation [6], which is the top priority and far more important than the 'economy' of glucose catabolism for ATP production. "
    Zhang S · Yang C · Yang Z · Zhang D · Ma X · Mills G · Liu Z ·

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    • "Experimental evidence in [24] also supports the existence of clusters in some YMO experiments. Since Saccharomyces cerevisiae is a model organism, it is important to understand the interconnectedness of the CDC and metabolism [1] [6] [15] [24] [27] [29]. Also, yeast are used in many bio-engineering processes and understanding their metabolism and cell cycle is of interest in some applications [14] [25] [31]. "
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    • "Their cell cycle is tightly restricted to the reductive phase of the metabolic cycle, which guarantees that DNA replication only occurs during glycolysis when the oxidative damage from respiration on the genome is minimal. Such a circadian rhythm that coordinates the metabolic and cell division cycles in situations where resources are limited, simply reflects an evolutionarily conserved means of preserving genome integrity (Chen et al., 2007). Silencing of a DNA checkpoint kinase abolishing such a rhythm allows DNA synthesis outside of the reductive phase but at the cost of increased spontaneous mutation rates. "
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