POLY(ADP-RIBOSE) SYNTHETASE ACTIVATION - AN EARLY INDICATOR OF NEUROTOXIC DNA-DAMAGE

DNA damage activates a nuclear enzyme poly(ADP-ribose) synthetase (PAR S) that facilitates DNA repair by adding multiple ADP-ribose groups to nuclear proteins such as histones and PARS itself. N-Methyl-D-asparta te neurotoxicity may involve DNA damage excessively activating PARS to deplete its substrate NAD, as PARS inhibitors prevent this toxicity. We now show that PARS is rapidly and markedly activated in PC12 cells following treatment with neurotoxic agents, including the amyloid beta -protein, hydrogen peroxide, N-methyl-4-phenyl-1,2,3,6-tetrahydropyrid ine (MPTP), and its active metabolite N-methyl-4-phenylpyridine (MPP()). With MPP(+), PARS activity is increased fivefold in 1 h and 20-fol d by 3 h. By contrast, direct measurement of DNA damage by the termina l-deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay shows no significant increase by 3 h and less than fourfold by 2 4 h. These findings indicate that PARS activity can provide a simple, sensitive, and early index of DNA damage following neurotoxic insults.