title: Delayed kinetics of DNA double-strand break processing in normal and pathological aging.
abstract: Accumulation of DNA damage may play an essential role in both cellular senescence and organismal aging. The ability of cells to sense and repair DNA damage declines with age. However, the underlying molecular mechanism for this age-dependent decline is still elusive. To understand quantitative and qualitative changes in the DNA damage response during human aging, DNA damage-induced foci of phosphorylated histone H2AX (gamma-H2AX), which occurs specifically at sites of DNA double-strand breaks (DSBs) and eroded telomeres, were examined in human young and senescing fibroblasts, and in lymphocytes of peripheral blood. Here, we show that the incidence of endogenous gamma-H2AX foci increases with age. Fibroblasts taken from patients with Werner syndrome, a disorder associated with premature aging, genomic instability and increased incidence of cancer, exhibited considerably higher incidence of gamma-H2AX foci than those taken from normal donors of comparable age. Further increases in gamma-H2AX focal incidence occurred in culture as both normal and Werner syndrome fibroblasts progressed toward senescence. The rates of recruitment of DSB repair proteins to gamma-H2AX foci correlated inversely with age for both normal and Werner syndrome donors, perhaps due in part to the slower growth of gamma-H2AX foci in older donors. Because genomic stability may depend on the efficient processing of DSBs, and hence the rapid formation of gamma-H2AX foci and the rapid accumulation of DSB repair proteins on these foci at sites of nascent DSBs, our findings suggest that decreasing efficiency in these processes may contribute to genome instability associated with normal and pathological aging.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. sedelnio@mail.nih.gov
authors.forename: Olga A
authors.initials: OA
authors.lastname: Sedelnikova
authors.forename: Izumi
authors.initials: I
authors.lastname: Horikawa
authors.forename: Christophe
authors.initials: C
authors.lastname: Redon
authors.forename: Asako
authors.initials: A
authors.lastname: Nakamura
authors.forename: Drazen B
authors.initials: DB
authors.lastname: Zimonjic
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Popescu
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics / Q000473:pathology* / Q000528:radiation effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D005720:Gamma Rays; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D008214:Lymphocytes / Q000502:physiology; D000076228:MRE11 Homologue Protein; D018613:Microscopy, Confocal; D008875:Middle Aged; D016615:Telomere; D000071857:Tumor Suppressor p53-Binding Protein 1; D014898:Werner Syndrome / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C121766:MRE11 protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes