**4.1. The possible functions of poly(ADP-ribosyl)ation on epigenetic regulation**

NAD+ not only plays important roles in DNA repair, mitochondrial functions, and cellular senescence [72, 100], but also affects the modification of chromatin proteins [77] and modulates the gene expression regulatory system [101]. More importantly, NAD+ is a substrate for the PARP enzyme to synthesize PAR macromolecules, which modify both PARP itself and chromosomal proteins and DNA repair factors [67]. Histones and HMGB (High mobility group box) proteins can be poly(ADP-ribosyl)ated [102–105], suggesting that modifications by such macromolecules on chromosomes affect the epigenetic regulation of the gene expression system. Moreover, poly(ADP-ribosyl)ation on the chromosomal insulator protein CTCF (CCCTC-binding factor) may be involved in epigenetic regulation [106, 107]. Recently, it was shown that CTCF binds directly to PAR to be recruited at DNA lesion sites, indicating that the CTCF also plays a role in the DNA damage response [108]. It has been suggested that poly(ADP-ribosyl)ation affects the methylation patterns in chromosomal DNAs [109, 110]. A recent study showed that the transcriptional regulation of the *EZH2* gene, which encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), by PARP1 [111], affects the methylation of chromatin proteins [112]. Because the incidence of cancer increases with aging [113], a decline in the cellular level of NAD+ , which might accompany the decrease in PARP activity [114]. SIRT1, which depends on the NAD+ molecule to de-acetylate histone proteins, plays important roles in the aging process [115]. Taken together, these observations imply that NAD+ and its polymerized form, PAR, are involved in epigenetic regulation, and that it may be altered in line with the aging process.
