Muiras M L, Müller M, Schächter F, Bürkle A
Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France.
J Mol Med (Berl). 1998 Apr;76(5):346-54. doi: 10.1007/s001090050226.
Poly(ADP-ribosyl)ation is a posttranslational modification of nuclear proteins which is catalyzed by poly(ADP-ribose) polymerase and represents an immediate response of eukaryotic cells to oxidative and other types of DNA damage. Previously a strong correlation had been detected between maximal poly(ADP-ribose) polymerase activity in permeabilized mononuclear leukocytes of various mammalian species and species-specific life span. To study a possible relation between longevity and poly(ADP-ribosyl)ation in humans we measured maximal oligonucleotide-stimulated poly(ADP-ribose) polymerase activity in permeabilized, Epstein-Barr virus transformed lymphoblastoid cell lines from a French population of 49 centenarians and 51 controls aged 20-70 years. Maximal enzyme activity was significantly higher in centenarians than in controls [median of controls: 9035 cpm/10(6) cells (lower quartile: 6156; upper quartile: 11,410); median of centenarians: 10,380 cpm/10(6) cells (lower quartile: 7994; upper quartile: 12,991); P=0.031 by Mann-Whitney U test]. In a subset of 16 controls and 24 centenarians, cellular poly(ADP-ribose) polymerase content was determined by quantitative western blotting, thus allowing the calculation of specific enzyme activity. The latter was significantly higher in centenarians (P=0.006), the median value for centenarians being about 1.6-fold that of controls. Specific poly(ADP-ribose) polymerase activity was a more powerful parameter for differentiating between centenarians and controls than enzyme activity relative to cell number. In addition, in a genetic association study we analyzed 437 DNA samples (239 centenarians and 198 controls) by PCR amplification of a polymorphic dinucleotide repeat located in the promoter region of the poly(ADP-ribose) polymerase gene in an attempt to detect an association between this polymorphic marker and variability of enzyme activity or human longevity. However, this genetic analysis revealed no significant enrichment of any of the alleles or genotypes identified among centenarians or controls, but its power was limited by the relatively weak heterozygosity of this polymorphic marker in our population (51%). Viewed together with previous results on poly(ADP-ribose) polymerase activity in various mammalian species, the present data provide further evidence for the notion that longevity is associated with a high poly(ADP-ribosyl)ation capacity.
聚（ADP - 核糖）化是一种核蛋白的翻译后修饰，由聚（ADP - 核糖）聚合酶催化，代表真核细胞对氧化及其他类型DNA损伤的即时反应。此前已在多种哺乳动物透化的单核白细胞中的最大聚（ADP - 核糖）聚合酶活性与物种特异性寿命之间检测到强相关性。为了研究人类寿命与聚（ADP - 核糖）化之间的可能关系，我们测量了来自法国49名百岁老人和51名20 - 70岁对照人群的透化的、爱泼斯坦 - 巴尔病毒转化的淋巴母细胞系中最大寡核苷酸刺激的聚（ADP - 核糖）聚合酶活性。百岁老人的最大酶活性显著高于对照组[对照组中位数：9035 cpm/10(6) 细胞（下四分位数：6156；上四分位数：11,410）；百岁老人中位数：10,380 cpm/10(6) 细胞（下四分位数：7994；上四分位数：12,991）；曼 - 惠特尼U检验P = 0.031]。在16名对照和24名百岁老人的子集中，通过定量蛋白质免疫印迹法测定细胞聚（ADP - 核糖）聚合酶含量，从而能够计算比酶活性。后者在百岁老人中显著更高（P = 0.006），百岁老人的中位数约为对照组的1.6倍。相对于细胞数量，聚（ADP - 核糖）聚合酶比酶活性是区分百岁老人和对照组的更有力参数。此外，在一项基因关联研究中，我们通过聚合酶链反应扩增位于聚（ADP - 核糖）聚合酶基因启动子区域的多态性二核苷酸重复序列，分析了437个DNA样本（239名百岁老人和198名对照），试图检测该多态性标记与酶活性或人类寿命变异性之间的关联。然而，该基因分析未发现百岁老人或对照组中鉴定出的任何等位基因或基因型有显著富集，但由于我们人群中该多态性标记的杂合度相对较低（51%），其检验效能有限。与先前关于多种哺乳动物聚（ADP - 核糖）聚合酶活性的结果一起考虑，目前的数据为寿命与高聚（ADP - 核糖）化能力相关这一观点提供了进一步证据。
