L-selegiline potentiates the cellular poly(ADP-ribosyl)ation response to ionizing radiation.
DNA strand breaks induced by alkylating agents, oxidants, or ionizing radiation trigger the covalent modification of nuclear proteins with poly(ADP-ribose), which is catalyzed for the most part by poly(ADP-ribose) polymerase-1 and plays a role in DNA base-excision repair. Poly(ADP-ribosyl)ation capacity of mononuclear blood cells correlates positively with life span of mammalian species. Here, we show that l-selegiline, an anti-Parkinson drug with neuroprotective activity and life span-extending effect in laboratory animals, can potentiate gamma-radiation-induced poly(ADP-ribose) formation in intact cells. COR4 hamster cells were incubated with l-selegiline (50 nM) for various time periods, followed by gamma-irradiation (45 Gy). Quantification of cellular poly(ADP-ribose) levels at 10 min after starting the irradiation revealed significant increases (up to 1.8-fold) in cells preincubated with the drug for 8 h to 7 days compared with drug-free irradiated controls. There was no selegiline-induced change in poly(ADP-ribose) levels of unirradiated cells nor in basal or radiation-induced DNA strand breaks, respectively. Surprisingly, poly(ADP-ribose) polymerase-1 protein was down-regulated by l-selegiline treatment. Addition of l-selegiline to purified poly(ADP-ribose) polymerase-1 did not alter enzymatic activity. In conclusion, the results of the present study identify a novel intervention to potentiate the cellular poly(ADP-ribosyl)ation response. We hypothesize that the effect of l-selegiline is due to modulation of accessory proteins regulating poly(ADP-ribose) polymerase-1 activity and that increased cellular poly- (ADP-ribosyl)ation capacity may contribute to the neuroprotective potential and/or life span extension afforded by l-selegiline.
Abteilung Tumorvirologie, Deutsches Krebforschungszentrum, Heidelberg, Germany.
Christine
C
Brabeck
Ragen
R
Pfeiffer
Alan
A
Leake
Sascha
S
Beneke
Ralph
R
Meyer
Alexander
A
Burkle
D000818:Animals; D006224:Cricetinae; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D018696:Neuroprotective Agents / Q000494:pharmacology; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011839:Radiation, Ionizing; D012642:Selegiline / Q000494:pharmacology*
D018696:Neuroprotective Agents; D011064:Poly Adenosine Diphosphate Ribose; D012642:Selegiline; D011065:Poly(ADP-ribose) Polymerases