| Autor: |
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 |
| Zdroj: |
Nature Cell Biology; 20230101, Issue: Preprints p1-13, 13p |
| Abstrakt: |
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. |
| Databáze: |
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