title: Structural chromosome abnormalities, increased DNA strand breaks and DNA strand break repair deficiency in dermal fibroblasts from old female human donors.
abstract: Dermal fibroblasts provide a paradigmatic model of cellular adaptation to long-term exogenous stress and ageing processes driven thereby. Here we addressed whether fibroblast ageing analysedex vivo entails genome instability. Dermal fibroblasts from human female donors aged 20-67 years were studied in primary culture at low population doubling. Under these conditions, the incidence of replicative senescence and rates of age-correlated telomere shortening were insignificant. Genome-wide gene expression analysis revealed age-related impairment of mitosis, telomere and chromosome maintenance and induction of genes associated with DNA repair and non-homologous end-joining, most notably XRCC4 and ligase 4. We observed an age-correlated drop in proliferative capacity and age-correlated increases in heterochromatin marks, structural chromosome abnormalities (deletions, translocations and chromatid breaks), DNA strand breaks and histone H2AX-phosphorylation. In a third of the cells from old and middle-aged donors repair of X-ray induced DNA strand breaks was impaired despite up-regulation of DNA repair genes. The distinct phenotype of genome instability, increased heterochromatinisation and (in 30% of the cases futile) up-regulation of DNA repair genes was stably maintained over several cell passages indicating that it represents a feature of geroconversion that is distinct from cellular senescence, as it does not encompass a block of proliferation.
authors: Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Med. Faculty, Düsseldorf, Germany.
authors: Faiza
authors: F
authors: Kalfalah
authors: Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Med. Faculty, Düsseldorf, Germany.|Institute of Human Genetics and Anthropology, Heinrich-Heine-University, Med. Faculty, Düsseldorf, Germany.
authors: Sabine
authors: S
authors: Seggewiß
authors: Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Med. Faculty, Düsseldorf, Germany.
authors: Regina
authors: R
authors: Walter
authors: Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors: Julia
authors: J
authors: Tigges
authors: Molecular Toxicology Group, Dept. of Biology, University of Konstanz, Konstanz, Germany.
authors: María
authors: M
authors: Moreno-Villanueva
authors: Molecular Toxicology Group, Dept. of Biology, University of Konstanz, Konstanz, Germany.
authors: Alexander
authors: A
authors: Bürkle
authors: Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
authors: Sebastian
authors: S
authors: Ohse
authors: Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.|German Cancer Research Centre (DFKZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors: Hauke
authors: H
authors: Busch
authors: Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.|German Cancer Research Centre (DFKZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors: Melanie
authors: M
authors: Boerries
authors: Institute of Human Genetics and Anthropology, Heinrich-Heine-University, Med. Faculty, Düsseldorf, Germany.
authors: Barbara
authors: B
authors: Hildebrandt
authors: Institute of Human Genetics and Anthropology, Heinrich-Heine-University, Med. Faculty, Düsseldorf, Germany.
authors: Brigitte
authors: B
authors: Royer-Pokora
authors: Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Med. Faculty, Düsseldorf, Germany.
authors: Fritz
authors: F
authors: Boege
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D002869:Chromosome Aberrations; D053960:DNA Breaks; D004260:DNA Repair; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D008875:Middle Aged; D055815:Young Adult