Evidence that exposure of the telomere 3' overhang sequence induces senescence.
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.
Li
Guang-Zhi
GZ
Department of Dermatology, Boston University School of Medicine, 609 Albany Street, J-Building, Boston, MA 02118-2394, USA.
Eller
Mark S
MS
Firoozabadi
Reza
R
Gilchrest
Barbara A
BA
D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D004249:DNA Damage; D006801:Humans; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000032:analysis; D020080:Tandem Repeat Sequences; D016615:Telomere; D035341:Telomeric Repeat Binding Protein 2 / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53