Poly(ADP-ribose): novel functions for an old molecule

Abstract

Poly(ADP-ribose) (PAR) is synthesized from NAD⁺ by PAR polymerases (PARPs) and regulates many physiological processes such as the maintenance of DNA integrity, gene expression and cell division. PARPs form a superfamily of 17 members in humans, and display diverse subcellular distributions and functions. Some members might function together and possess overlapping properties. PAR that is synthesized in response to DNA-strand breaks is a DNA-damage signalling molecule that allows a rapid and efficient cellular evaluation of the damage range. It is also an essential recruiting molecule that, in a few seconds, concentrates key factors of the single-strand break repair pathway at the site of the lesion. The poly(ADP-ribosyl)ation of histones that are associated with open chromatin conformation at the DNA-damage site provided the first clue to the roles of PAR as an epigenetic modification. Recent evidence revealed an important role of PAR in the epigenetic regulation of chromatin structure and in gene expression under physiological conditions in which the integrity of the DNA is not affected. The dogma that the DNA-damage-dependent PARP-1 is activated by DNA-strand breaks has to be reconsidered now due to recent studies that showed the activation of PARP-1 in the absence of DNA interruptions. Elucidating the triggers is currently one of our most exciting challenges. PARP-1 and PAR play key roles in various acute and chronic inflammatory disorders as well as in a number of degenerative diseases by contributing to the caspase-independent, apoptosis-inducing factor (AIF)-dependent cell death. PARP inhibition confers protection to these pathologies. PARP inhibitors have promising pharmacological applications in potentializing the effect of antitumour drugs in cancer therapy as well as in the treatment of inflammatory, neurological and cardiac disorders. Emerging evidence indicates a possible functional interplay between the PAR metabolic pathway and the SIRT1-mediated deacetylation pathway in the regulation of chromatin structure and function that is associated with broad biological activities.