NAD+ regulates nucleotide metabolism and genomic DNA replication

• Published in: Nature cell biology Vol. 25; no. 12; pp. 1774 - 1786
• Main Authors: Munk, Sebastian Howen Nesgaard, Merchut-Maya, Joanna Maria, Adelantado Rubio, Alba, Hall, Arnaldur, Pappas, George, Milletti, Giacomo, Lee, MyungHee, Johnsen, Lea Giørtz, Guldberg, Per, Bartek, Jiri, Maya-Mendoza, Apolinar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2023
• Subjects: 13/31; 14/19; 14/63; 38/91; 631/337/151/1431; 631/337/1644; 82/58; Biomedical and Life Sciences; Cancer Research; Cell Biology; Developmental Biology; Life Sciences; Medicin och hälsovetenskap; Stem Cells
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-023-01280-z

The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD + ) is essential for maintaining metabolic homeostasis and preserving genomic integrity. As a co-enzyme, NAD + plays a key role in regulating metabolic pathways, such as glycolysis and Kreb’s cycle. ADP-ribosyltransferases (PARPs) and sirtuins rely on NAD + to mediate post-translational modifications of target proteins. The activation of PARP1 in response to DNA breaks leads to rapid depletion of cellular NAD + compromising cell viability. Therefore, the levels of NAD + must be tightly regulated. Here we show that exogenous NAD + , but not its precursors, has a direct effect on mitochondrial activity. Short-term incubation with NAD + boosts Kreb’s cycle and the electron transport chain and enhances pyrimidine biosynthesis. Extended incubation with NAD + results in depletion of pyrimidines, accumulation of purines, activation of the replication stress response and cell cycle arrest. Moreover, a combination of NAD + and 5-fluorouridine selectively kills cancer cells that rely on de novo pyrimidine synthesis. We propose an integrated model of how NAD + regulates nucleotide metabolism, with relevance to healthspan, ageing and cancer therapy. Munk et al. show that exogenous NAD + , but not its precursors, induces metabolic changes in mitochondria affecting nucleotide metabolism with impacts on genomic DNA synthesis and genome integrity.