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Arch Biochem Biophys. 2002 Jun 15;402(2):227-34.

The inhibition of poly(ADP-ribose) polymerase enhances growth rates of ataxia telangiectasia cells.

Author information

1
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

Abstract

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.

PMID:
12051667
DOI:
10.1016/S0003-9861(02)00078-4
[Indexed for MEDLINE]

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