# Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention
## 2 The Influence of NAD+ Status on Genomic Stability and Cell Senescence
### NAD+ Influences Cell Signaling by Acting as Substrate of NAD+-Consuming Enzymes  
NAD+ may regulate genome stability and senescence acting as a substrate for the poly-ADP-ribose polymerase (PARP) enzymes, NAD+-dependent deacetylases of the Sirtuin family (SIRTs), and cyclic ADP-ribose synthases (cADPRSs), which can function as NAD-glycolrolases (Figure 1). PARPs and SIRTs are enzymes that accomplish two key posttranslational modifications, i.e., poly-ADP-ribosylation (PARylation) and acetylation, respectively. Therefore, all these enzymes share NAD+ as common substrate and compete for its consumption. Moreover, these reactions release NAM that can be an endogenous inhibitor of both PARPs and SIRTs [2; 4; 17]. PARP-1 is the most common PARP, and is ubiquitously expressed. PARP-1 is as sensor of DNA breakage and has several roles in DNA damage responses, including DNA repair, maintenance of genomic stability, transcriptional regulation, signaling pathways involving apoptosis, telomere functions, and other multiple cellular functions [18; 19]. PARP-1 is involved in maintaining a compact status and preventing accidental transcription [20]. Activated PARP-1 may favor DNA damage repair by either physical association or by PARylation of specific proteins, including single-strand break-repair proteins, BER enzymes, and itself. PARP-1 is activated by binding to DNA strand breaks. The PARylation of proteins proximal to breaks modifies their structure favoring the opening of the condensed chromatin and the recruitment of DNA repair complexes [19]. Furthermore, PARP-1 plays a key role in DNA repair through its association with NER and BER enzymes [17; 19; 21]. The intensity of DNA damage determines PARP-mediated cell response. Following mild or moderate DNA damage, activation of PARP-1 leads to DNA repair and restoration of normal cellular function [4]. When the damage is irreparable, PARP-1 facilitates apoptosis, preventing ATP depletion and DNA repair through PARP-1 caspase-mediated cleavage. However, persistent DNA damage leads to over-activation of PARP-1 and increased NAD+ catabolism causing suppression of NAD+-dependent ATP generation, energy crisis, and necrotic cell death [22]. SIRTs are NAD+-dependent deacetylase enzymes that remove acetyl, succinyl, and other similar groups from proteins. SIRTs controls several cellular processes, including transcription through histone epigenomic modulations, mitochondrial biogenesis, inflammation, cellular resistance to genotoxic insults, and metabolic dysfunctions [23; 24]. SIRT1 plays a critical role in skin homeostasis, aging, and cancer [23]. The increase of the NAD+/NADH ratio enhances SIRT1 activity resulting in deacetylation of its targets, including the tumor suppressor protein p53 and the FOXO forkhead family of transcription factors. Conversely, low NAD+ levels decrease SIRT activity [23; 25]. Cell survival following DNA damage may depend on SIRT1 activation intensity. p53 drives transcription of several genes triggering cell-cycle arrest, apoptosis, or DNA repair and its activity increases following DNA damage [23]. Moderate SIRT1 activation prevents apoptosis through p53 deacetylation that leads to its inhibition. However, continuous SIRT1 activation may induce cell death by accelerated NAD+ depletion [26]. Following genotoxic stress, PARP-1 and SIRT1 antagonistically interplay regulating energetic homeostasis, genomic integrity and inflammation. Indeed, they share NAD+ and several other substrates, including DNA repair enzymes and NF-kB. Persistent PARP-1 activation can either reduce NAD+ levels and raise NAM level, thus inhibiting SIRT1 activity. Similarly, the activation of SIRT1 reduces PARP activity. Moreover, PARP-1 inhibition prevents NAD+ depletion, restores the ATP levels, and activates SIRT1. Following oxidative stress, PARP-1 directly binds OGG1 that, in turn, stimulates PARP-1 activity. Moreover, activation of PARP-1 negatively regulates OGG1 activity [27].