丹麦癌症研究所Apolinar Maya-Mendoza和Jiri Bartek研究组合作揭示了烟酰胺腺嘌呤二核苷酸(NAD+)调节核苷酸代谢和基因组DNA复制。该项研究成果发表在2023年11月13日出版的《自然—细胞生物学》上。

他们表明外源性NAD+，而不是其前体，对线粒体活性有直接影响。与NAD+短期孵育促进Kreb循环和电子传递链，并促进嘧啶生物合成。与NAD+长期孵育导致嘧啶的消耗，嘌呤的积累，复制应激反应的激活和细胞周期停滞。此外，NAD+和5-氟吡啶的组合选择性地杀死依赖于重新合成嘧啶的癌细胞。他们提出了一个NAD+如何调节核苷酸代谢的综合模型，与健康、衰老和癌症治疗相关。

据悉，包括NAD+在内的复杂的酶活性编排对于维持代谢稳态和保持基因组完整性至关重要。作为一种辅酶，NAD+在糖酵解和Kreb循环等代谢途径的调节中起着关键作用。ADP -核糖基转移酶(PARPs)和sirtuins依赖于NAD+介导靶蛋白的翻译后修饰。PARP1在DNA断裂时的激活会导致细胞NAD+的快速消耗，从而损害细胞的生存能力。因此，必须严格调节NAD+的水平。

附：英文原文

Title: NAD+ regulates nucleotide metabolism and genomic DNA replication

Author: Munk, Sebastian Howen Nesgaard, Merchut-Maya, Joanna Maria, Adelantado Rubio, Alba, Hall, Arnaldur, Pappas, George, Milletti, Giacomo, Lee, MyungHee, Johnsen, Lea Girtz, Guldberg, Per, Bartek, Jiri, Maya-Mendoza, Apolinar

Issue&Volume: 2023-11-13

Abstract: 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.

DOI: 10.1038/s41556-023-01280-z

Source: https://www.nature.com/articles/s41556-023-01280-z