title: 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.
abstract: 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.
authors.affiliation: Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Cottet
authors.forename: H
authors.initials: H
authors.lastname: Blanché
authors.forename: P
authors.initials: P
authors.lastname: Verasdonck
authors.forename: I
authors.initials: I
authors.lastname: Le Gall
authors.forename: F
authors.initials: F
authors.lastname: Schächter
authors.forename: A
authors.initials: A
authors.lastname: Bürkle
authors.forename: M L
authors.initials: ML
authors.lastname: Muiras
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D005260:Female; D005602:France; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary
chemical_list: D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases