Induction of Apoptosis by Telomere 3′ Overhang-Specific DNA

Eller, Mark S.; Puri, Neelu; Hadshiew, Ina M.; Venna, Suraj; Gilchrest, Barbara A.

doi:10.1006/excr.2002.5531

Cited by 77 publications

(199 citation statements)

References 45 publications

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“…These responses include apoptosis (34), p95͞Nbs1 phosphorylation (35), and cell-cycle arrest (35,39). We propose that exposure of this 3Ј-overhang sequence in the nucleus after telomere loop disruption is the physiologic trigger for these responses, and that T-oligos, known to accumulate in the nucleus (34,39,40), mimic this signal (Fig. 5).…”

Section: Resultsmentioning

confidence: 96%

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

Eller

Firoozabadi

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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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.DNA damage ͉ aging

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Section: Resultsmentioning

confidence: 96%

“…We have shown recently that T-oligos induce an S-phase arrest within 24 h in normal and transformed cells, mediated by phosphorylation of the p95͞Nbs1 protein (34,35). To better define the cell-cycle arrest in T-oligo-induced senescence, fibroblasts were treated for 1 week and then collected for cell-cycle analysis and Western analysis.…”

Section: Resultsmentioning

confidence: 99%

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

Eller

Firoozabadi

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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144

177

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“…These data provide an explanation for phenomena initially reported by Krauss and colleagues [5,6] who showed that CHO-K1 cells containing a corrected eGFP gene score positive for cell cycle arrest. Previous work by Gilchrest and colleagues [10][11][12] demonstrated that specific oligonucleotides bearing sequences resembling 3' telomeric DNA induce a stalling of DNA replication and cell senescence as a result of a p53-mediated SOS response.…”

Section: Introductionmentioning

confidence: 99%

Recovery of cell cycle delay following targeted gene repair by oligonucleotides

et al. 2007

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We have previously shown that activation of the homologous recombinational repair pathway leads to a block of cell division in corrected cells, possibly through the activity of checkpoint proteins Chk1 and Chk2. In this study, we examine the long term impact of this stalling on the growth of cells that have enabled gene repair events. Using a mutated eGFP gene as an episomal reporter, we show that corrected (eGFP positive) cells contain only a few active replication templates two weeks after electroporation, yet do not display an apoptotic or senescent phenotype. By six weeks after electroporation, cells resume active replication with a cell cycle profile that is comparable to that of the non-corrected (eGFP negative) population. These results indicate that the initial stalling is transient and eGFP positive cells eventually resume a normal phenotypic growth pattern, allowing for passaging and expansion in vitro.

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“…We have found that providing cultured cells with DNA oligonucleotides substantially homologous to the telomere sequence, which we term T-oligos, mimics telomere loop disruption, leading to ATM/p53 signaling (38) and the DNA damage-like responses of senescence (39) or apoptosis (40) but apparently without disruption of the loop or other effects on genomic DNA (40). Because these 2-11-base T-oligos concentrate rapidly in the nucleus (40,41), we hypothesize that T-oligos are interpreted by the cell as indicating telomere loop disruption, specifically exposure of the otherwise concealed 3Ј-overhang sequence (38 -40), and hence initiate signaling for DNA damage-like responses without antecedent DNA damage.…”

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confidence: 99%

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

Marwaha

Chen

Helms

et al. 2005

Journal of Biological Chemistry

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Chronically irradiated murine skin and UV light-induced squamous cell carcinomas overexpress the inducible isoform of cyclooxygenase (COX-2), and COX-2 inhibition reduces photocarcinogenesis in mice. We have reported previously that DNA oligonucleotides substantially homologous to the telomere 3-overhang (T-oligos) induce DNA repair capacity and multiple other cancer prevention responses, in part through up-regulation and activation of p53. To determine whether T-oligos affect COX-2 expression, human newborn keratinocytes and fibroblasts were pretreated with T-oligos or diluent alone for 24 h, UVirradiated, and processed for Western blotting. In both cell types, T-oligos transcriptionally down-regulated base-line and UV light-induced COX-2 expression, coincident with p53 activation. In fibroblasts with wild type versus dominant negative p53 (p53 WT versus p53 DN ), T-oligos decreased constitutive expression of a COX-2 reporter plasmid by >50%. We then examined NFB, a known positive regulator of COX-2 transcription. In p53 WT but not in p53 DN fibroblasts and in human keratinocytes, T-oligos decreased readout of an NFB promoter-driven reporter plasmid and decreased NFB binding to DNA. After T-oligo treatment and subsequent UV irradiation, binding of the transcriptional co-activator protein p300 to NFB was decreased, whereas binding of p300 to p53 was increased. Human skin explants provided with T-oligos had markedly decreased COX-2 immunostaining both at base-line and post-UV light, coincident with increased p53 immunostaining. We conclude that T-oligos transcriptionally down-regulate COX-2 expression in human skin via activation and up-regulation of p53, at least in part by inhibiting NFB transcriptional activation. Decreased COX-2 expression may contribute to the observed ability of T-oligos to reduce photocarcinogenesis.Nonmelanoma skin cancer accounts for well over 1 million cases of human malignancy annually in the United States, and the incidence continues to rise (1-3). The major initiator and promoter of skin cancer is UVB radiation (4, 5). Among the contributing effects of UVB radiation on skin are the formation of cyclobutane-pyrimidine dimers and pyrimidine (6-4) photoproducts (6, 7), which lead to mutations in key regulatory genes (8), epidermal hyperplasia (9, 10) allowing for expansion of mutated clones (11), immunosuppression (12, 13), and inflammation (14, 15).One way inflammation in particular is thought to affect carcinogenesis is by promoting epidermal hyperplasia and proliferation through production of cytokines and various second messengers such as prostaglandin E 2 (16). The major enzyme responsible for the UVB-induced prostaglandin synthesis is cyclooxygenase-2 (COX-2), 5 the inducible isoform of the cyclooxygenase enzyme (17) that carries out the ratelimiting step of prostaglandin and thromboxane production (18 -20). COX-2 has been shown to be overexpressed in numerous human malignancies, including colon, lung, and breast cancers (21-24). In relation to skin cancer, UVB irradiation increas...

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Induction of Apoptosis by Telomere 3′ Overhang-Specific DNA

Cited by 77 publications

References 45 publications

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

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

Recovery of cell cycle delay following targeted gene repair by oligonucleotides

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

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