Abstract

Poly(ADP-ribosyl)ation is functionally associated with DNA base-excision repair and is a survival factor and negative regulator of genomic instability in cells under low to moderate levels of genotoxic stress [1]. Previously we have described a positive correlation between poly(ADP-ribosyl)ation capacity of mononuclear blood cells with longevity of mammalian species [2]. Our subsequent comparisons of purified recombinant human and rat PARP-1 revealed that this correlation might be explained in part by evolutionary sequence divergence [3]. We have also reported an association of high poly(ADP-ribosyl)ation capacity of lymphoblastoid cell cultures with longevity of human donors [4]. Recently we have asked if the efficiency of single strand-break repair in mononuclear blood cells following gamma-radiation might also be related with mammalian life span. We quantified DNA strand breaks both immediately after irradiation and after a defined postincubation (‘repair’) period, using a recently developed automated version of the fluorescence-detected alkaline unwinding assay. Our data reveal the existence of a highly significant positive correlation between the extent of repair and life span of donor species [5]. In another set of experiments we have investigated the possible effects of L-selegiline on the cellular poly(ADP-ribosyl)ation response. L-selegiline is an anti-Parkinson drug, which irreversibly inhibits monoamine oxidase B (MAO-B) but possesses additional effects, such as neuroprotective activity in vivo and in cultured cells and life span-extension in laboratory animals. Intriguingly, our data show that low concentrations of L-selegiline can potentiate the gamma-radiation-induced poly(ADP-ribose) formation in cultured hamster cells [6], thus strengthening the links between poly(ADP-ribosyl)ation, cytoprotection and mammalian longevity.References: 1.Bürkle A: Cancer Lett, 2001; 163: 1-5 2.Grube K, Bürkle A: Proc Natl Acad Sci USA, 1992; 89: 11759-11763 3.Beneke S, Alvarez-Gonzalez R, Bürkle A: Exp Gerontol, 2000; 35: 989-1002 4.Muiras ML, Müller M, Schächter F, Bürkle A: J Mol Med, 1998; 76: 346-354 5.Pfeiffer R, Leake A, Müller M, Kirkwood TB, Bürkle A: manuscript in preparation. 6.Brabeck C, Pfeiffer R, Leake L, Beneke S, Meyer R, Bürkle A: submitted.

Keywords: PARP-1, DNA strand breaks, DNA Repair, ageing, life span, L-selegiline