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

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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.