Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening.
H2O2 has been the most commonly used inducer for stress-induced premature senescence (SIPS), which shares features of replicative senescence. However, there is still uncertainty whether SIPS and replicative senescence differ or utilize different pathways. 'Young' human diploid fibroblasts (HDFs), treated with prolonged low doses of hydrogen peroxide, led to irreversible cellular senescence. Cells exhibited senescent-morphological features, irreversible G1 cell cycle arrest and irreversible senescence-associated beta-galactosidase positivity. The appearance of these cellular senescence markers was accompanied by significant increases of p21, gadd45 expression and p53 binding activity, as well as a significant decline in DNA repair capability and accelerated telomere shortening. Our results suggest that multiple pathways might be involved in oxidative SIPS, including genes related to DNA-damage-and-repair and telomere shortening, and that SIPS shares the same mechanisms with replicative senescence in vivo. Our findings indicate that several aging theories can be merged together by a common mechanism of oxidative damage, and that the level of oxidative DNA-damage-and-repair capacity may be exploited as reliable markers of cell senescence.
Duan
Jianming
J
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China.
Duan
Jianping
J
Zhang
Zongyu
Z
Tong
Tanjun
T
D018797:Cell Cycle Proteins / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D020552:Comet Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004171:Diploidy; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018384:Oxidative Stress; D016615:Telomere / Q000187:drug effects / Q000648:ultrastructure*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D001616:beta-Galactosidase / Q000378:metabolism; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006861:Hydrogen Peroxide; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase; D000097642:GADD45 Proteins; C493956:CDKN1A protein, human