title: Increased chromosome instability and accumulation of DNA double-strand breaks in Werner syndrome cells.
abstract: Werner syndrome (WS) is a premature aging syndrome caused by mutations of the WRN gene. Here, we demonstrate that a strain of WS fibroblast cells shows abnormal karyotypes characterized by several complex translocations and 50-fold more frequency of abnormal metaphases including dicentric chromosomes without fragments than normal cells when examined at a similar culture stage. Further, telomere fluorescence in situ hybridization indicates that the abnormal signals, extra telomere signal and loss of telomere signal, emerge two- to three-fold more frequently in WS cells than in normal cells. Taken together, these results indicate that chromosome instability including dysfunction of telomere maintenance is more prominent in WS cells than in normal cells. In addition, the accumulation of DNA double-strand breaks (DSBs) at the G(1) phase, including those at telomeres, detected by phosphorylated ATM (ataxia telangiectasia mutated) foci is accelerated in WS cells even at a low senescence level. The increased accumulation of DSBs in WS cells is reduced in the presence of anti-oxidative agents, suggesting that enhanced oxidative stress in WS cells is involved in accelerated accumulation of DSBs. These results indicate that WS cells are prone to accumulate DSBs spontaneously due to a defect of WRN, which leads to increased chromosome instability that could activate checkpoints, resulting in accelerated senescence.
authors: Laboratory of Radiation Biology, Research Reactor Institute, Kyoto University.
authors: Kentaro
authors: K
authors: Ariyoshi
authors: Keiji
authors: K
authors: Suzuki
authors: Makoto
authors: M
authors: Goto
authors: Masami
authors: M
authors: Watanabe
authors: Seiji
authors: S
authors: Kodama
mesh_terms: D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D014898:Werner Syndrome / Q000235:genetics* / Q000473:pathology*