DNA damage response activates respiration and thereby enlarges dNTP pools to promote cell survival in budding yeast

The DNA damage response (DDR) is an evolutionarily conserved process essential for cell survival. Previously, we found that decreased histone expression induces mitochondrial respiration, raising the question whether the DDR also stimulates respiration. Here, using oxygen consumption and ATP assays, RT-qPCR and ChIP-qPCR methods, and dNTP analyses, we show that DDR activation in the budding yeast Saccharomyces cerevisiae, either by genetic manipulation or by growth in the presence of genotoxic chemicals, induces respiration. We observed that this induction is conferred by reduced transcription of histone genes and globally decreased DNA nucleosome occupancy. This globally altered chromatin structure increased the expression of genes encoding enzymes of tricarboxylic acid cycle, electron transport chain, oxidative phosphorylation, elevated oxygen consumption, and ATP synthesis. The elevated ATP levels resulting from DDR-stimulated respiration drove enlargement of dNTP pools; cells with a defect in respiration failed to increase dNTP synthesis and exhibited reduced fitness in the presence of DNA damage. Together, our results reveal an unexpected connection between respiration and the DDR and indicate that the benefit of increased dNTP synthesis in the face of DNA damage outweighs possible cellular damage due to increased oxygen metabolism.