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Poly(ADP-ribosyl)ation: its role in inducible DNA amplification, and its correlation with the longevity of mammalian species

A Bürkle, K Grube, J H Küpper
Experimental and Clinical Immunogenetics 1992, 9 (4): 230-40
1307244
In this paper, we review our recent work on poly(ADP-ribosyl)ation and its relationships with DNA amplification and with the life span of different mammalian species. Poly(ADP-ribosyl)ation is a eukaryotic posttranslational protein modification catalyzed by poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30). This enzyme is strongly activated by DNA strand breaks and apparently plays a role in DNA repair and other cellular responses to DNA damage. Our data from two different cell culture systems for inducible DNA amplification strongly suggest that poly(ADP-ribosyl)ation acts as a negative regulatory factor in the DNA amplification induced by carcinogens. Furthermore, we could show a strong positive correlation between directly stimulated PARP activities in mononuclear leukocytes of 13 mammalian species and the species' maximal life spans. The hypothesis is raised that a higher poly(ADP-ribosyl)ation capacity of long-lived species might contribute to the efficient maintenance of genome integrity and stability over their longer life span. Finally, we could show that the selectively overexpressed PARP DNA-binding domain efficiently inhibits poly(ADP-ribosyl)ation in a transdominant manner. This molecular genetic approach should permit further interventional studies on biological role(s) of poly(ADP-ribosyl)ation without application of low-molecular-weight PARP inhibitors, thus avoiding any of their possible side effects.

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