The tumor suppressor p53 acts as a master transcription factor that controls hundreds of effecter genes in response to various cellular stresses. The flexibility of p53 to regulate its target genes with distinct functions (growth arrest, DNA repair, apoptosis etc.) is largely conferred by extensive and dynamic posttranslational modifications of the protein, including phosphorylation, acetylation, methylation, ubiquitination, sumoylation, neddylation and ADP-ribosylation. Recent evidence suggests that acetylation is indispensable for p53 activation. A major regulator of p53 acetylation, and hence p53 function, is a group of Class III histone deacetylases known as Sirtuins (SIRTs), that utilize nicotinamide adenine dinucleotide (NAD+) as substrate to catalyze the removal of acetyl groups from p53, resulting in the “silencing” of p53 activity. In an effort to determine whether a feedback loop exists whereby p53 is involved in the regulation of NAD+ metabolism, nicotinamide adenylyltransferase 2 (Nmnat2), a key NAD+ synthetase, was identified to be a novel target gene of p53, from which two transcript variants are expressed in human (TV1 and TV2). Two putative p53 response elements within the first intronic region of human Nmnat2 gene were also identified that can actively drive the expression of luciferase reporter gene in a p53-dependent manner. Most importantly, data suggests that Nmnat2, like SIRTs, is involved in the regulation of p53-mediated apoptosis and protein acetylation upon DNA damage. Furthermore, Nmnat2 isoforms exert opposite functions on SIRT-mediated deacetylation of p53. Specifically, ectopic expression of Nmnat2 TV2 isoform promotes p53 acetylation after DNA damage, whereas ectopic expression of Nmnat2-TV1 isoform suppresses it. Manipulation of SIRT activities by either RNA interference or specific inhibitors modifies p53 acetylation status the same way Nmnat2-TV2 isoform does. Collectively, the results suggest the existence of a p53-Nmnat2 feedback loop, whereby p53 can regulate its own activity positively or negatively, depending on the nature and extent of DNA damage.