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.
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
Cayetano
C
Von Kobbe
Alfred
A
May
Carla
C
Grandori
Vilhelm A
VA
Bohr
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