NAD+ regulates nucleotide metabolism and genomic DNA replication

Sebastian Howen Nesgaard Munk, Joanna Maria Merchut-Maya, Alba Adelantado Rubio, Arnaldur Hall, George Pappas, Giacomo Milletti, Myung Hee Lee, Lea Giørtz Johnsen, Per Guldberg, Jiri Bartek*, Apolinar Maya-Mendoza*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

Original languageEnglish
JournalNature Cell Biology
Issue number12
Pages (from-to)1774-1786
Publication statusPublished - Dec 2023


  • DNA Replication
  • Genomics
  • Glycolysis
  • Metabolic Networks and Pathways
  • NAD/metabolism


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