Bürkle A, Grube K, Küpper J H
Forschungsschwerpunkt Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, BRD.
Exp Clin Immunogenet. 1992;9(4):230-40.
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.
在本文中，我们回顾了我们最近关于聚（ADP-核糖基）化及其与DNA扩增以及不同哺乳动物物种寿命之间关系的研究工作。聚（ADP-核糖基）化是一种由聚（ADP-核糖）聚合酶（PARP；EC 2.4.2.30）催化的真核生物翻译后蛋白质修饰。这种酶被DNA链断裂强烈激活，并且显然在DNA修复和其他细胞对DNA损伤的反应中发挥作用。我们来自两种不同的可诱导DNA扩增细胞培养系统的数据强烈表明，聚（ADP-核糖基）化在致癌物诱导的DNA扩增中起负调节因子的作用。此外，我们能够证明，在13种哺乳动物的单核白细胞中直接刺激的PARP活性与这些物种的最大寿命之间存在很强的正相关性。由此提出一个假设，即长寿物种较高的聚（ADP-核糖基）化能力可能有助于在其较长的寿命期间有效地维持基因组的完整性和稳定性。最后，我们能够证明，选择性过表达的PARP DNA结合结构域以反式显性方式有效地抑制聚（ADP-核糖基）化。这种分子遗传学方法应该允许在不应用低分子量PARP抑制剂的情况下，对聚（ADP-核糖基）化的生物学作用进行进一步的干预研究，从而避免其任何可能的副作用。
