The inhibition of poly(ADP-ribose) polymerase enhances growth rates of ataxia telangiectasia cells.
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which is activated in response to genotoxic insults by binding damaged DNA and attaching polymers of ADP-ribose to nuclear proteins at the expense of its substrate NAD+. In persons affected with ataxia telangiectasia (A-T), associated mutations in the ataxia telangiectasia mutated gene render cells unable to cope with the genotoxic stresses from ionizing radiation and oxidative damage, thus resulting in a higher concentration of unrepaired DNA damage and the activation of PARP in an uncontrolled manner. In primary A-T fibroblasts, we observed a 58-96% increase in PARP activity and a concomitant loss of cellular NAD+ and ATP content. PARP protein by Western blot analysis increased only slightly in these cells, supporting the observation that the steady state levels of DNA damage is higher in A-T cells than in normals. When treated with PARP inhibitors 3-aminobenzamide or 1,5-dihydroisoquinoline, cellular growth rates reached those observed in normal fibroblast cultures. The improvement of cellular growth and NAD+ levels in A-T cells with PARP inhibition suggests that the cellular metabolic status of A-T cells is compromised and the inhibition of PARP may relieve some of the drain on cellular pyridine nucleotides and ATP. Thus, therapy utilizing PARP inhibitors may provide a benefit for individuals affected with A-T.
Marecki
John C
JC
Department of Biochemistry and Molecular Genetics, Webb Waring Institute for Cancer, Aging and Antioxidant Research, University of Colorado Health Sciences Center, Denver, CO 80262, USA. john.marecki@uchsc.edu
McCord
Joe M
JM
D000255:Adenosine Triphosphate / Q000378:metabolism; D001260:Ataxia Telangiectasia / Q000201:enzymology* / Q000473:pathology*; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
C459809:1,5-dihydroisoquinoline; D001549:Benzamides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate