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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Evidence that exposure of the telomere 3' overhang sequence induces senescence.
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Evidence that exposure of the telomere 3' overhang sequence induces senescence.

机译：端粒3'突出端序列的暴露引起衰老的证据。

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摘要

Normal human cells cease proliferation after a finite number of population doublings, a phenomenon termed replicative senescence. This process, first convincingly described by Hayflick and Moorhead [Hayflick, L. & Moorhead, P. S. (1961) Exp. Cell Res. 25, 595-621] for cultured human fibroblasts 40 years ago, is suggested to be a fundamental defense against cancer. Several events have been demonstrated to induce the senescent phenotype including telomere shortening, DNA damage, oxidative stress, and oncogenic stimulation. The molecular mechanisms underlying senescence are poorly understood. Here we report that a 1-week exposure to oligonucleotide homologous to the telomere 3'-overhang sequence TTAGGG (T-oligo) similarly specifically induces a senescent phenotype in cultured human fibroblasts, mimicking serial passage or ectopic expression of a dominant negative form of the telomeric repeat binding factor, TRF2(DN). We propose that exposure of the 3' overhang due to telomere loop disruption may occur with critical telomere shortening or extensive acute DNA damage and that the exposed TTAGGG tandem repeat sequence then triggers DNA-damage responses. We further demonstrate that these responses can be induced by treatment with oligonucleotides homologous to the overhang in the absence of telomere disruption, a phenomenon of potential therapeutic importance.
机译：正常的人类细胞在有限数量的种群倍增后停止增殖，这种现象称为复制性衰老。该过程首先由Hayflick和Moorhead令人信服地描述[Hayflick，L.＆Moorhead，P. S.（1961）Exp。 Cell Res。 [25，595-621]被认为是40年前培养的人类成纤维细胞的基本防御方法。已经证明了几种诱导衰老表型的事件，包括端粒缩短，DNA损伤，氧化应激和致癌性刺激。衰老的分子机制了解甚少。在这里我们报告说，与端粒3'-突出端序列TTAGGG（T-oligo）同源的寡核苷酸暴露1周类似地在培养的人成纤维细胞中特异性地诱导衰老表型，模仿了其主要负型的连续传代或异位表达。端粒重复结合因子TRF2（DN）。我们建议由于严重的端粒缩短或广泛的急性DNA损伤，可能发生由于端粒环破坏引起的3'突出端的暴露，并且暴露的TTAGGG串联重复序列随后触发DNA损伤反应。我们进一步证明，在端粒不存在的情况下，可以通过用与突出端同源的寡核苷酸进行治疗来诱导这些应答，这是一种潜在的治疗重要性现象。

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