ARH3, a Therapeutic Target for Cancer, Ischemia, and Inflammation

ADP-ribosylation is important in many cellular processes, including DNA replication and repair, maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. Poly-ADP-ribose is important in a number of critical physiological processes such as DNA repair, cellular differentiation, and carcinogenesis. Until recently, only one human enzyme, PARG, had been identified that degrades the ADP-ribose polymer. Another ADP-ribose, O-acetyl-ADP ribose, is formed via the deacetylation of proteins, such as acetyl-histone, by proteins in the Sir2 family. Sir2 proteins have been implicated in regulation of chromatin structure and longevity.

The NIH announces the discovery of a novel PARG-like enzyme, ARH3. ARH3 possesses PARG activity, yet is structurally distinct from PARG. ARH3 also hydrolyzes O-acetyl-ADP-ribose, and is the only protein recognized to date with such activity. ARH3 thus appears to function in two important signaling pathways, serving to regulate both poly-ADP-ribose and O-acetyl-ADP-ribose levels. It may affect chromatin structure through effects on both pathways. Since ARH3 structures differs from PARG or other enzymes that participate in these pathways, it may be possible to design specific inhibitors to target both the poly-ADP-ribose and Sir2 pathways. These drugs may be used as anticancer agents, radiosensitizers or antiviral agents, or for treating disorders involving oxidative damage, such as acute tissue injury, ischemia, and inflammation.