Gorbunova Vera, Seluanov Andrei, Pereira-Smith Olivia M
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.
J Biol Chem. 2002 Oct 11;277(41):38540-9. doi: 10.1074/jbc.M202671200. Epub 2002 Jul 24.
Cells subjected to sub-lethal doses of stress such as irradiation or oxidative damage enter a state that closely resembles replicative senescence. What triggers stress-induced premature senescence (SIPS) and how similar this mechanism is to replicative senescence are not well understood. It has been suggested that stress-induced senescence is caused by rapid telomere shortening resulting from DNA damage. In order to test this hypothesis directly, we examined whether overexpression of the catalytic subunit of human telomerase (hTERT) can protect cells from SIPS. We therefore analyzed the response of four different lines of normal human fibroblasts with and without hTERT to stress induced by UV, gamma-irradiation, and H(2)O(2). SIPS was induced with the same efficiency in normal and hTERT-immortalized cells. This suggests that SIPS is not triggered by telomere shortening and that nonspecific DNA damage serves as a signal for induction of SIPS. Although telomerase did not protect cells from SIPS, fibroblasts expressing hTERT were more resistant to stress-induced apoptosis and necrosis. We hypothesize that healing of DNA breaks by telomerase inhibits the induction of cell death, but because healing does not provide legitimate DNA repair, it does not protect cells from SIPS.
受到亚致死剂量应激（如辐射或氧化损伤）的细胞会进入一种与复制性衰老极为相似的状态。应激诱导的早衰（SIPS）的触发因素以及该机制与复制性衰老的相似程度尚不清楚。有人提出，应激诱导的衰老由DNA损伤导致的端粒快速缩短引起。为了直接验证这一假设，我们检测了人端粒酶催化亚基（hTERT）的过表达是否能保护细胞免受SIPS影响。因此，我们分析了四种不同的正常人成纤维细胞系（有无hTERT）对紫外线、γ辐射和H₂O₂诱导的应激的反应。正常细胞和hTERT永生化细胞中SIPS的诱导效率相同。这表明SIPS不是由端粒缩短触发的，非特异性DNA损伤是诱导SIPS的信号。虽然端粒酶不能保护细胞免受SIPS影响，但表达hTERT的成纤维细胞对应激诱导的凋亡和坏死更具抗性。我们推测，端粒酶对DNA断裂的修复抑制了细胞死亡的诱导，但由于这种修复不能提供合法的DNA修复，所以它不能保护细胞免受SIPS影响。
