Evidence that exposure of the telomere 3′ overhang sequence induces senescence

被引:123
作者
Li, GZ [1 ]
Eller, MS [1 ]
Firoozabadi, R [1 ]
Gilchrest, BA [1 ]
机构
[1] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA
关键词
DNA damage; aging;
D O I
10.1073/pnas.0235444100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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 oligonucleotid\es homologous to the overhang in the absence of telomere disruption, a phenomenon of potential therapeutic importance.
引用
收藏
页码:527 / 531
页数:5
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