Inhibition of Poly(ADP-Ribosyl)ation Allows DNA Hypermethylation

Abstract

This chapter emphasizes that along the chain of events that induce DNA methylation-dependent chromatin condensation, a post-synthetic modification other than histone acetylation, poly(ADP-ribosyl)ation, participates in the establishment and maintenance of methylation-free regions of chromatin. In fact, several lines of in vitro and in vivo evidence have shown that poly(ADP-ribosyl)ation is involved in the control of DNA methylation pattern, protecting genomic DNA from full methylation. More recent studies have provided some clues to the understanding of the molecular mechanism(s) connecting poly(ADP-ribosyl)ation with DNA methylation. We aim here to demonstrate the direct correlation existing between inhibition of poly(ADP-ribose) polymerases and DNA hypermethylation, and to describe some possible mechanisms underlying this molecular link. We will then present our hypothesis that the inhibition of the poly(ADP-ribosyl)ation process in the cell may be responsible for the anomalous hypermethylation of oncosuppressor gene promoters during tumorigenesis and to suggest the possibility that an active poly(ADP-ribosyl)ation process is also involved in maintaining the unmethylated state of CpG islands in normal cells.