Role of nicotinamide in DNA damage, mutagenesis, and DNA repair

Abstract

Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD(+)), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerous in vitro and in vivo studies have clearly shown that PARP-1 and NAD(+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability.

Figure 1

Figure 2

The simplified pathways for nicotinamide, niacin, NAD⁺, and PARP-1 metabolism. Dietary nicotinamide, niacin, and tryptophan are precursors for the synthesis of NAD⁺, essential in ATP production and PARP-1 activation. Nicotinamide can be converted to niacin by bacterial nicotinamidase in the intestinal lumen. PARP-1 is activated by DNA strand breaks, cleaving NAD⁺ into nicotinamide and ADP-ribose. Poly(ADP-ribose) glycohydrolase (PARG) reactivates PARP-1 by removing poly(ADP-ribose)polymers, allowing for continuous NAD⁺ utilization. Figure is adapted from Jacobson et al., in 1995 [6] and Meyer-Ficca et al., in 2004 [12].

Figure 3

PARP-1 and cellular responses to DNA damage. The intensity of DNA damage determines cellular pathways: survival, apoptosis, or necrosis. In the case of mild DNA damage, poly(ADP-ribosylation) enhances DNA repair and thus cell survival. When the damage is beyond repair, PARP-1 facilitates apoptosis, preventing ATP depletion and DNA repair through PARP-1 caspase-mediated cleavage. Severe DNA damage leads to PARP-1 overactivation, cellular energy depletion, and necrotic cell death. Figure is adapted from Virág and Szabó, in 2002 [70].