Article

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

ABSTRACT

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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    • "On the basis of their work with the distiller's strain IFO 0233, Klevecz and colleagues first suggested that the observed gating between YMC and CDC might be functionally important for the temporal separation of CDC events (i.e., DNA replication) that are incompatible with YMC events (i.e., HOC and aerobic respiration, which could lead to oxidative damage of DNA; Klevecz et al., 2004). This was confirmed by subsequent work with a different laboratory strain, CEN.PK, which showed that DNA replication occurred toward the end of HOC as pO 2 levels rise (Tu et al., 2005; Chen et al., 2007). The authors classified the end of HOC (when yeast oxygen consumption is still high) as a " reductive-building " phase, based on clustering of gene expression microarrays. "
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    ABSTRACT: Cells have evolved oscillators with different frequencies to coordinate periodic processes. Here, we studied the interaction of two oscillators, the cell division cycle (CDC) and yeast metabolic cycle (YMC), in budding yeast. Previous work suggested that the CDC and YMC interact to separate high oxygen consumption from DNA replication to prevent genetic damage. To test this hypothesis, we grew diverse strains in chemostat and measured DNA replication and oxygen consumption with high temporal resolution at different growth rates. Our data showed that high oxygen consumption is not strictly separated from DNA replication; rather, cell cycle Start is coupled with the initiation of high oxygen consumption and catabolism of storage carbohydrates. The logic of this YMC-CDC coupling may be to ensure that DNA replication and cell division occur only when sufficient cellular energy reserves have accumulated. Our results also uncovered a quantitative relationship between CDC period and YMC period across different strains. More generally, our approach shows how studies in genetically diverse strains efficiently identify robust phenotypes and steer the experimentalist away from strain-specific idiosyncrasies.
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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. "

    Full-text · Dataset · Nov 2015
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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. "

    Full-text · Article · Mar 2015
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