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.
· Development of therapeutics for cancer or disorders associated with excessive DNA damage
· Development of therapeutics for diseases involving oxidative damage, such as acute tissue injury, ischemia and inflammation
· Patients with chemotherapy-resistant tumors, or with cancers that are genetically deficient in DNA repair
· Patients with inflammatory or ischemia/reperfusion diseases, particularly those associated with acute cardiovascular disease
1. S Oka, J Kato, J Moss. Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase. J Biol Chem. 2006 Jan 13;281(2):705-713 . [PubMed abs]
2. T Ono, A Kasamatsu, S Oka, J Moss. The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylases. Proc Natl Acad Sci USA 2006 Nov 7;103(45):16687-16691. Epub 2006 Oct 30, doi 10.1073/pnas.0607911103. [PubMed abs]
· U.S. Provisional Application No. 60/716,807 filed 12 Sep 2005 (HHS Reference No. E-347-2004/0-US-01)
· PCT Application No. PCT/US2006/035771 filed 12 Sep 2006 (HHS Reference No. E-347-2004/0-PCT-02)
Joel Moss et al. (NHLBI)
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