Sequence divergence and diversity suggests ongoing functional diversification of vertebrate NAD metabolism

Gossmann, Toni I.; Ziegler, Mathias

doi:10.1016/j.dnarep.2014.07.005

Cited by 15 publications

(12 citation statements)

References 77 publications

(110 reference statements)

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“…This was recently corroborated by the observation that VEEV and SARS macrodomain-containing proteins can efficiently reverse PARP10-derived RNA ADP-ribosylation in vitro (Munnur et al 2019). Noteworthy, this aspect of viral-induced stress may create evolutionary pressure and thus contribute to the rapid positive selection observed in antiviral PARPs (Daugherty et al 2014;Gossmann and Ziegler 2014). Expression of PARP9, PARP12-14 is potently stimulated by interferon type I in response to viral infection (Juszczynski et al 2006;Schoggins et al 2011;Welsby et al 2014), thus suggesting that ADP-ribosylation signaling is required for an efficient viral response.…”

Section: Viral and Microbial Macrodsmentioning

confidence: 82%

(ADP-ribosyl)hydrolases: structure, function, and biology

2020

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ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life. Its complexity derives from the varied range of different chemical linkages, including to several amino acid side chains as well as nucleic acids termini and bases, it can adopt. In this review, we provide an overview of the different families of (ADP-ribosyl)hydrolases. We discuss their molecular functions, physiological roles, and influence on human health and disease. Together, the accumulated data support the increasingly compelling view that (ADP-ribosyl)hydrolases are a vital element within ADP-ribosyl signaling pathways and they hold the potential for novel therapeutic approaches as well as a deeper understanding of ADP-ribosylation as a whole.

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Section: Viral and Microbial Macrodsmentioning

confidence: 82%

(ADP-ribosyl)hydrolases: structure, function, and biology

2020

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“…The question arises whether and how NAD + metabolism can be targeted for cancer therapy. NAD + is synthesized through multiple routes [24]. In humans, the central pathway relies on nucleobases with special preference for nicotinamide (Nam), although nicotinic acid (NA) can also serve as starting material for NAD + synthesis [25].…”

Section: Introductionmentioning

confidence: 99%

Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

Kiss

Ráduly

Regdon

et al. 2020

Cancers

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Osteosarcoma (OS) is the most common bone tumor in children and adolescents. Modern OS treatment, based on the combination of neoadjuvant chemotherapy (cisplatin + doxorubicin + methotrexate) with subsequent surgical removal of the primary tumor and metastases, has dramatically improved overall survival of OS patients. However, further research is needed to identify new therapeutic targets. Here we report that expression level of the nuclear NAD synthesis enzyme, nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1), increases in U-2OS cells upon exposure to DNA damaging agents, suggesting the involvement of the enzyme in the DNA damage response. Moreover, genetic inactivation of NMNAT1 sensitizes U-2OS osteosarcoma cells to cisplatin, doxorubicin, or a combination of these two treatments. Increased cisplatin-induced cell death of NMNAT1−/− cells showed features of both apoptosis and necroptosis, as indicated by the protective effect of the caspase-3 inhibitor z-DEVD-FMK and the necroptosis inhibitor necrostatin-1. Activation of the DNA damage sensor enzyme poly(ADP-ribose) polymerase 1 (PARP1), a major consumer of NAD+ in the nucleus, was fully blocked by NMNAT1 inactivation, leading to increased DNA damage (phospho-H2AX foci). The PARP inhibitor, olaparib, sensitized wild type but not NMNAT1−/− cells to cisplatin-induced anti-clonogenic effects, suggesting that impaired PARP1 activity is important for chemosensitization. Cisplatin-induced cell death of NMNAT1−/− cells was also characterized by a marked drop in cellular ATP levels and impaired mitochondrial respiratory reserve capacity, highlighting the central role of compromised cellular bioenergetics in chemosensitization by NMNAT1 inactivation. Moreover, NMNAT1 cells also displayed markedly higher sensitivity to cisplatin when grown as spheroids in 3D culture. In summary, our work provides the first evidence that NMNAT1 is a promising therapeutic target for osteosarcoma and possibly other tumors as well.

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“…2B denote the average number of NAD-dependent signaling enzyme families found in each clade (a detailed distribution is provided in SI Appendix, Table S2). With the exception of Cnidaria and Lophotrochozoa, we noted an average of 3 to 4 families in protostomes, whereas most deuterostome species have, on average, more than 8 families, with an increasing diversification of enzymes within some of these families, especially PARPs (43).…”

Section: Paradoxical Evolutionary Correlation Between Nad-dependent Smentioning

confidence: 72%

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Bockwoldt

Houry

Niere

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. NAD-dependent signaling (e.g., by sirtuins and poly–adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.

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Sequence divergence and diversity suggests ongoing functional diversification of vertebrate NAD metabolism

Cited by 15 publications

References 77 publications

(ADP-ribosyl)hydrolases: structure, function, and biology

(ADP-ribosyl)hydrolases: structure, function, and biology

Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

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