Poly(ADP-ribosyl)ation: its role in inducible DNA amplification, and its correlation with the longevity of mammalian species.
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.
Bürkle
A
A
Forschungsschwerpunkt Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, BRD.
Grube
K
K
Küpper
J H
JH
D000818:Animals; D016466:CHO Cells / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D005057:Eukaryotic Cells / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D008136:Longevity / Q000502:physiology*; D008322:Mammals / Q000502:physiology*; D011064:Poly Adenosine Diphosphate Ribose / Q000502:physiology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013045:Species Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011993:Recombinant Fusion Proteins; D011064:Poly Adenosine Diphosphate Ribose; D004247:DNA; D013762:Tetrahydrofolate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases