Induction of apoptosis by telomere 3' overhang-specific DNA.
Telomeres are tandem repeats of a specific TTAGGG nucleotide sequence at the ends of chromosomes. Telomere shortening is proposed to act as a biological clock and cancer prevention mechanism by inducing a nonproliferative, senescent phenotype after a limited number of cellular divisions. Recent evidence also suggests that telomere disruption can trigger apoptosis in certain cell types, mimicking a major cellular response to DNA damage. Here, we show that addition of DNA oligonucleotides homologous to the telomere 3' overhang sequence causes lymphocytic (Jurkat) cells to undergo apoptosis, as described for lymphocytes following telomere loop disruption. We further implicate the p53 tumor suppressor and transcription factor, as well as the p53 homolog p73 and the E2F1 transcription factor, in mediating the apoptotic response. We propose that exposure of the telomere 3' overhang due to opening of the normal telomere loop structure is a physiologic signal for these DNA damage-like responses in vivo and that oligonucleotides partially or completely homologous to the telomere overhang mimic this signal in the absence of DNA damage or telomere disruption.
Eller
Mark S
MS
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.
Puri
Neelu
N
Hadshiew
Ina M
IM
Venna
Suraj S
SS
Gilchrest
Barbara A
BA
D024509:3' Flanking Region / Q000187:drug effects / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001483:Base Sequence / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D004247:DNA / Q000235:genetics* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005057:Eukaryotic Cells / Q000187:drug effects / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D019169:Jurkat Cells; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D016615:Telomere / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013936:Thymidine / Q000235:genetics / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; D009841:Oligonucleotides; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; D013936:Thymidine