Extensive allelic variation and ultrashort telomeres in senescent human cells

Baird, Duncan Martin; Rowson, J. M.; Wynford-Thomas, David; Kipling, David

doi:10.1038/ng1084

Cited by 478 publications

(517 citation statements)

References 28 publications

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“…4,6-Diamidino-2-phenylindole staining of squash preparations detected the presence of cells (57.4 ± 8.7%, mean ± s.d., Po0.001 compared with control mice) with aberrant nuclei in tumor tissue from 70124-treated mice (Figure 8f). Furthermore, tumor cells from mice treated with the inhibitor showed a threefold reduction (Po0.0001) in telomeric signal intensity for individual nuclei compared with untreated mice, indicating a decrease in telomere length (Figure 8g), which is known to trigger cell cycle arrest and replicative senescence in human cells (Baird et al, 2003). Additionally, 46.1±11.4% (mean±s.d.)…”

Section: Treatment With 70124 Induces Tumor Cell Senescence In Mice Xmentioning

confidence: 97%

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

et al. 2011

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Glioblastoma multiforme is one of the most devastating cancers and presents unique challenges to therapy because of its aggressive behavior. Cancer-initiating or progenitor cells have been described to be the only cell population with tumorigenic capacity in glioblastoma. Therefore, effective therapeutic strategies targeting these cells or the early precursors may be beneficial. We have established different cultures of glioblastoma-initiating cells (GICs) derived from surgical specimens and found that, after induction of differentiation, the NFjB transcriptional pathway was activated, as determined by analyzing key proteins such as p65 and IjB and the upregulation of a number of target genes. We also showed that blockade of nuclear factor (NF)jB signaling in differentiating GICs by different genetic strategies or treatment with smallmolecule inhibitors, promoted replication arrest and senescence. This effect was partly mediated by reduced levels of the NFjB target gene cyclin D1, because its downregulation by RNA interference reproduced a similar phenotype. Furthermore, these results were confirmed in a xenograft model. Intravenous treatment of immunodeficient mice bearing human GIC-derived tumors with a novel smallmolecule inhibitor of the NFjB pathway induced senescence of tumor cells but no ultrastructural alterations of the brain parenchyma were detected. These findings reveal that activation of NFjB may keep differentiating GICs from acquiring a mature postmitotic phenotype, thus allowing cell proliferation, and support the rationale for therapeutic strategies aimed to promote premature senescence of differentiating GICs by blocking key factors within the NFjB pathway.

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Section: Treatment With 70124 Induces Tumor Cell Senescence In Mice Xmentioning

confidence: 97%

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

et al. 2011

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“…A more detailed analysis of telomere lengths was carried out using single telomere length analysis (STELA) (Baird et al, 2003) (Figure 5c, supplementary Figure). Analysis of the XpYp telomere confirmed that hTERT þ cells had longer telomeres than hTERTÀ cells.…”

Section: Metal-induced Genomic Instabilitymentioning

confidence: 99%

“…STELA DNA extractions and STELA reactions were carried out as previously described (Baird et al, 2003), with the following adaptations: The Taq/Pwo ratio was adjusted from 25:1 to 10:1 and we cycled the reactions with an MJ PTC-225 thermocycler (MJ research) under the following conditions: 22 cycles of 941C for 15 s, 651C for 30 s and 681C for 10 min. To ensure specificity of telomeric bands only those that hybridized to both the telomere-adjacent and telomere-repeat containing probe were analysed.…”

Section: Cell-cycle Analysismentioning

confidence: 99%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

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There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longerterm genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERTÀ cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased b-galactosidase staining and apoptosis. This instability was not present in telomerasepositive hTERT þ cells. In contrast, in hTERT þ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERTÀ cells. The growth and survival of both metal-exposed hTERT þ and hTERTÀ cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

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“…In human beings, telomere shortening contributes to mortality in many age-related diseases (34). Notably, it is reported that some alleles show almost complete loss of TTAGGG repeats in senescence (35). Thus, telomere shortening has been suggested to be a 'molecular clock' of the aging process.…”

Section: The Role Of Reactive Oxygen Species In Agingmentioning

confidence: 99%

Sequence-specific DNA damage by reactive oxygen species: Implications for carcinogenesis and aging

Oikawa

2005

Environ Health Prev Med

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Reactive oxygen species (ROS) generated by environmental chemicals can cause sequence-specific DNA damage, which may lead to carcinogenesis and aging. We investigated the mechanism of DNA damage by environmental chemicals (catechol, propyl gallate and bisphenol-A), homocysteine and UVA radiation using human cultured cell lines and 32 P-labeled DNA fragments. Carcinogenic catechol induced piperidine-labile sites frequently at thymine residues in the presence of Cu(II) and NADH. Furthermore, catechol increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, but not in HP100, a hydrogen peroxide (H 2 O 2 )-resistant cell line derived from HL-60. Thus, it is concluded that oxidative DNA damage through generation of H 2 O 2 plays an important role in the carcinogenic process of catechol. In addition, an environmental factor, bisphenol-A, and a dietary factor, propyl gallate, also induced sequence-specific DNA damage via ROS generation.UVA, as well as UVB, contributes to photoaging. In humans, telomere shortening is believed to be associated with cell senescence. In this study, we investigated the shortening rate of telomeres in human WI-38 fibroblasts exposed to UVA irradiation. The telomere length (as measured by terminal restriction fragment length) in WI-38 fibroblasts irradiated with UVA decreased with increasing the irradiation dose. UVA irradiation with riboflavin caused damage specifically at the GGG sequence in the DNA fragments containing telomere sequence (TTAGGG) 4 . We concluded that the GGG-specific damage in telomere sequence induced by UVA irradiation participates in the increase of the telomere shortening rate.In this report, we show our experimental results and discuss the mechanisms of sequence-specific DNA damage in relation to carcinogenesis and aging.

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Extensive allelic variation and ultrashort telomeres in senescent human cells

Cited by 478 publications

References 28 publications

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

Effects of hTERT on metal ion-induced genomic instability

Sequence-specific DNA damage by reactive oxygen species: Implications for carcinogenesis and aging

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