02 May 2003 : Original article
Evaluation of poly(ADP-ribose) glycohydrolase (PARG) as a therapeutic target for modulation of cellular responses to genotoxic stress
M. Jacobson, R. Meyer, M. Meyer-Ficca, D. Coyle, H. Kim, M. Oliveira, J. Slama, E. JacobsonMed Sci Monit 2003; 9(1): 29-0 :: ID: 15083
Abstract
Proteins are reversibly modified with ADP-ribose polymers by the combined action of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG). The activation of PARP-1 and PARP-2 following genotoxic stress leads to rapid polymer synthesis, rapid polymer turnover as a result of PARG activity, and it can lead to depletion of cellular NAD. DNA break-activated PARPs are promising targets for the modulation of cellular responses to genotoxic stress and the closely coordinated activities of PARPs and PARG indicates that PARG may also be a good therapeutic target. We have approached target validation of PARG using several approaches. The cloning and expression of the cDNA coding for bovine [1] and human [2] PARG has allowed structural characterizations that make possible molecular genetic approaches to PARG modulation. Photoaffinity labeling and site-directed mutagenesis has led to the identification of three acidic residues essential for catalytic activity, allowing the expression of dominant negative forms of PARG. The cDNA sequence has allowed the design of RNA interference approaches for modulating PARG activity. The discovery of a sensitive and selective inhibitor of PARG [3], ADP-HPD, has led to the synthesis of a cell permeable inhibitor that can be used to modulate PARG activity in cultured cells. This presentation will compare the efficiency of the different approaches in modulating PARG activity and the effects of PARG modulation on NAD and ADP-ribose polymer metabolism and biological responses to genotoxic stress. Supported by grants from the NIH (CA-43894) and Niadyne, Inc. RGM was supported by NIH Cancer Biology Training Grant CA-09213.References: 1.Lin et al: J Biol Chem, 1997; 272: 11895-11901 2.Meyer et al: 2003, submitted 3.Slama et al: J Med Chem, 1995; 38: 389-393
Keywords: Poly(ADP-ribose) glycohydrolase, PARG, therapeutic targets, genotoxic stress
Editorial
01 May 2024 : Editorial
Editorial: First Regulatory Approval for Adoptive Cell Therapy with Autologous Tumor-Infiltrating Lymphocytes (TILs) – Lifileucel (Amtagvi)DOI: 10.12659/MSM.944927
Med Sci Monit 2024; 30:e944927
In Press
11 Mar 2024 : Clinical Research
Enhancement of Frozen-Thawed Human Sperm Quality with Zinc as a Cryoprotective AdditiveMed Sci Monit In Press; DOI: 10.12659/MSM.942946
12 Mar 2024 : Database Analysis
Risk Factors of Age-Related Macular Degeneration in a Population-Based Study: Results from SHIP-TREND-1 (St...Med Sci Monit In Press; DOI: 10.12659/MSM.943140
12 Mar 2024 : Clinical Research
Preoperative Blood Transfusion Requirements for Hemorrhoidal Severe Anemia: A Retrospective Study of 128 Pa...Med Sci Monit In Press; DOI: 10.12659/MSM.943126
12 Mar 2024 : Clinical Research
Tissue Inhibitors of Metalloproteinase 1 (TIMP-1) and 3 (TIMP-3) as New Markers of Acute Kidney Injury Afte...Med Sci Monit In Press; DOI: 10.12659/MSM.943500
Most Viewed Current Articles
17 Jan 2024 : Review article
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
14 Dec 2022 : Clinical Research
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
16 May 2023 : Clinical Research
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952