Signaling pathway requirements for induction of senescence by telomere homolog oligonucleotides.
Cellular senescence is a major defense against cancer. In human fibroblasts, suppressing both the p53 and pRb pathways is necessary to bypass replicative senescence as well as senescence induced by ectopic expression of a dominant negative form of the telomere repeat binding factor 2, TRF2(DN). We recently reported that exposure to oligonucleotides homologous to the telomere 3' overhang (T-oligos) activates both the p53 and pRb pathways and leads to senescence in primary human fibroblasts. To further characterize T-oligo-induced senescence, we compared established isogenic fibroblast cell lines lacking functional p53 and/or pRb pathways to the normal parental line. Here, we report that, as in physiologic senescence, inactivation of both the p53 and pRb pathways is necessary to suppress T-oligo-induced senescence. Moreover, T-oligo rapidly induces senescence in a malignant fibroblast-derived cell line, demonstrating the potential of using T-oligo as a novel anticancer therapeutic. Our data support the hypothesis that exposure of the TTAGGG tandem repeat telomere 3' overhang sequence is the event that initiates signaling through DNA damage response pathways after experimental telomere disruption, serial passage, or acute genomic damage of normal cells.
Li
Guang-Zhi
GZ
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118-2394, USA.
Eller
Mark S
MS
Hanna
Kendra
K
Gilchrest
Barbara A
BA
D001483:Base Sequence; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage; D006801:Humans; D009841:Oligonucleotides / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016615:Telomere / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
D009841:Oligonucleotides; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53