Cottet F, Blanché H, Verasdonck P, Le Gall I, Schächter F, Bürkle A, Muiras M L
Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France.
J Mol Med (Berl). 2000;78(8):431-40. doi: 10.1007/s001090000132.
Poly(ADP-ribose) polymerase-1 (PARP-1) encoded by the PARP-1 gene, is a ubiquitous and abundant DNA-binding protein involved in the cellular response to various genotoxic agents. In a previous study we showed that maximal oligonucleotide-stimulated poly(ADP-ribosyl)ation was significantly higher in permeabilised lymphoblastoid cell lines from a French population of centenarians compared with controls aged 20-70 years, supporting the notion that longevity is associated with a genetically determined, high poly(ADP-ribosyl)ation capacity. Here, we describe four new genetic polymorphisms, three of which represent silent nucleotide variants (C402T, T1011C, G1215A), and one of which leads to a valine762-to-alanine exchange (T2444C). We undertook an association study between two of these polymorphisms and human longevity or poly(ADP-ribosyl)ation capacity in permeabilised lymphoblastoid cells. By analysing 648 DNA samples from a French population (324 centenarians and 324 controls) by fluorescent-allele-specific PCR, we showed the absence of any significant enrichment of any of the genotypes in the study of centenarians versus controls. Furthermore, we studied genotype distributions from individuals who had previously been tested for poly(ADP-ribosyl)ation capacity. None of the genotype combinations at any polymorphic site studied could be related to a high or low level of poly(ADP-ribosyl)ation capacity. Together, these results strongly suggest that the longevity-related differences in the poly(ADP-ribosyl)ation capacity of human lymphoblastoid cell lines cannot be explained by genetic polymorphisms in the PARP-1 coding sequence and that other mechanisms have to be considered as potential regulators of specific poly(ADP-ribosyl)ation capacity.
由PARP - 1基因编码的聚（ADP - 核糖）聚合酶-1（PARP - 1）是一种普遍存在且含量丰富的DNA结合蛋白，参与细胞对各种基因毒性剂的反应。在先前的一项研究中，我们发现，与20 - 70岁的对照组相比，来自法国百岁老人群体的透化淋巴母细胞系中，最大寡核苷酸刺激的聚（ADP - 核糖基）化显著更高，这支持了长寿与遗传决定的高聚（ADP - 核糖基）化能力相关的观点。在此，我们描述了四种新的基因多态性，其中三种是沉默核苷酸变体（C402T、T1011C、G1215A），另一种导致缬氨酸762到丙氨酸的交换（T2444C）。我们对其中两种多态性与人类长寿或透化淋巴母细胞中的聚（ADP - 核糖基）化能力进行了关联研究。通过荧光等位基因特异性PCR分析来自法国人群的648个DNA样本（324名百岁老人和324名对照），我们发现在百岁老人与对照的研究中，任何基因型均未出现显著富集。此外，我们研究了先前已检测聚（ADP - 核糖基）化能力的个体的基因型分布。在所研究的任何多态性位点，没有任何基因型组合与高或低水平的聚（ADP - 核糖基）化能力相关。总之，这些结果强烈表明，人类淋巴母细胞系聚（ADP - 核糖基）化能力中与长寿相关的差异不能用PARP - 1编码序列中的基因多态性来解释，并表明必须考虑其他机制作为特定聚（ADP - 核糖基）化能力的潜在调节因子。
