New polymorphisms in the human poly(ADP-ribose) polymerase-1 coding sequence: lack of association with longevity or with increased cellular poly(ADP-ribosyl)ation capacity

Poly(ADP-ribose) polymerase-1 (PARP-1) encoded by the PARP-1 gene, is a ubi quitous and abundant DNA-binding protein involved in the cellular response to various genotoxic agents. In a previous study we showed that maximal oli gonucleotide-stimulated poly(ADP-ribosyl)ation was significantly higher in permeabilised lymphoblastoid cell lines from a French population of centena rians compared with controls aged 20-70 years, supporting the notion that l ongevity is associated with a genetically determined, high poly(ADP-ribosyl )ation capacity. Here, we describe four new generic polymorphisms, three of which represent silent nucleotide variants (C402T, T1011C, G(1215)A), and one of which leads to a valine(762)-to-alanine exchange (T2444C). We undert ook an association study between two of these polymorphisms and human longe vity or poly(ADP-ribosyl)ation capacity in permeabilised lymphoblastoid cel ls. By analysing 648 DNA samples from a French population (324 centenarians and 324 controls) by fluorescent-allele-specific PCR, we showed the absenc e of any significant enrichment of any of the genotypes in the study of cen tenarians versus controls. Furthermore, we studied genotype distributions f rom individuals who had previously been tested for poly(ADP-ribosyl)ation c apacity. 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 differ ences in the poly(ADP-ribosyl)ation capacity of human lymphoblastoid cell l ines cannot be explained by genetic polymorphisms in the PARP-1 coding sequ ence and that other mechanisms have to be considered as potential regulator s of specific poly(ADP-ribosyl)ation capacity.