Werner syndrome cells escape hydrogen peroxide-induced cell proliferation arrest.
Werner syndrome (WS) is a rare disease caused by the lack of a functional nuclear WS protein (WRN). WS is characterized by the early onset of premature aging signs and a high incidence of sarcomas. WS diploid fibroblasts have a short life span and extensive genomic instability. Mammalian cells are continuously exposed to reactive oxygen species (ROS), which represent human mutagens and are thought to be a major contributor to the aging process. Hydrogen peroxide (H2O2) is a common ROS intermediate generated by various forms of oxidative stress. In response to H2O2-induced DNA damage, normal human diploid fibroblasts follow a pathway leading to irreversible proliferation arrest and premature senescence. Here we show that in contrast to normal human fibroblasts, WS diploid fibroblasts continue proliferating after extensive H2O2-induced DNA damage and accumulate oxidative DNA lesions. A direct role of WRN in this abnormal cellular response to H2O2 is demonstrated by interfering with WRN expression in normal human fibroblasts. We propose a role for WRN in the detection and/or processing of oxidative DNA lesions and in cellular responses to H2O2 as they relate to some of the phenotypical aspects of WS cells.
Von Kobbe
Cayetano
C
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
May
Alfred
A
Grandori
Carla
C
Bohr
Vilhelm A
VA
D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D010084:Oxidation-Reduction; D053484:RecQ Helicases; D014898:Werner Syndrome / Q000235:genetics* / Q000378:metabolism; D000071657:Werner Syndrome Helicase
D004247:DNA; D006861:Hydrogen Peroxide; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase