Telomeres in dyskeratosis congenita

Shay, Jerry W.; Wright, Woodring E.

doi:10.1038/ng0504-437

Cited by 35 publications

(23 citation statements)

References 14 publications

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“…Thus, telomeres are the molecular clock that counts the number of times a cell has divided, and telomeres determine when cellular senescence [M1] and crisis [M2] occurs 61, 62. Several human diseases of telomere dysfunction have been discovered 63–71, and individuals born with reduced levels of telomerase have short telomeres. This leads to telomere dysfunction in highly proliferative cells, such as the bone marrow, resulting in diseases such as aplastic anaemia and, in some instances (likely in combination with additional genetic and epigenetic changes), increased risk for the development of leukemia 63–71.…”

Section: Telomerasementioning

confidence: 99%

Hallmarks of telomeres in ageing research

Shay

Wright

2007

The Journal of Pathology

188

173

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Telomeres are repetitive DNA sequences at the ends of linear chromosomes. Telomerase, a cellular reverse transcriptase, helps maintain telomere length in human stem cells, reproductive cells and cancer cells by adding TTAGGG repeats onto the telomeres. However, most normal human cells do not express telomerase and thus each time a cell divides some telomeric sequences are lost. When telomeres in a subset of cells become short (unprotected), cells enter an irreversible growth arrest state called replicative senescence. Cells in senescence produce a different constellation of proteins compared to normal quiescent cells. This may lead to a change in the homeostatic environment in a tissue-specific manner. In most instances cells become senescent before they can become cancerous; thus, the initial growth arrest induced by short telomeres may be thought of as a potent anti-cancer protection mechanism. When cells can be adequately cultured until they reach telomerebased replicative senescence, introduction of the telomerase catalytic protein component (hTERT) into telomerase-silent cells is sufficient to restore telomerase activity and extend cellular lifespan. Cells with introduced telomerase are not cancer cells, since they have not accumulated the other changes needed to become cancerous. This indicates that telomeraseinduced telomere length manipulations may have utility for tissue engineering and for dissecting the molecular mechanisms underlying genetic diseases, including cancer.

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Section: Telomerasementioning

confidence: 99%

Hallmarks of telomeres in ageing research

Shay

Wright

2007

The Journal of Pathology

188

173

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“…Importantly, GRN163 is not a typical antisense oligonucleotide targeting mRNA. Because it is a direct enzymatic inhibitor at the hTR active site, RNase H is not required and a 50% inhibition of target can lead to telomere dysfunction (14). GRN163-induced telomere erosion also causes the induction of senescence or apoptosis in prostate cancer, multiple myeloma, and non-Hodgkins lymphoma cells as well as a reduction of tumor growth in myeloma and glioblastoma xenograft models (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Antiadhesive Effects of GRN163L—An Oligonucleotide N3′→P5′ Thio-Phosphoramidate Targeting Telomerase

et al. 2007

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We determined previously that a novel human telomerase RNA (hTR) antagonist, GRN163L, inhibited the tumorigenic potential of A549-luciferase (A549-luc) lung cancer cells in vitro and in vivo. Further studies revealed that A549-luc cells were also morphologically altered by GRN163L. A549-luc cells treated before cell attachment with a single dose of GRN163L only weakly attached to the substrate and remained rounded, whereas control mismatch-treated cells exhibited typical epitheloid appearance and adhesion properties. These morphologic changes were independent of hTR expression and telomerase inhibition and were unrelated to telomere length. This effect is dependent on the molecular properties of the lipid moiety, the phosphorothioate backbone, and the presence of triplet-G sequences within the GRN163L structure. Altered adhesion was manifested by a 50% reduction in rapid cellular attachment and a 3-fold decrease in total cell spreading surface area. Administration of a single dose of GRN163L (15 mg/kg) at the time of cell inoculation, using an in vivo model of lung cancer metastasis, resulted in significant reductions in tumor burden at days 13, 20, and 27 of tumor progression. Thus, the potent antimetastatic effects of GRN163L may be related, in part, to the antiadhesive effects of this novel cancer therapeutic conferred via specific structural determinants and that these effects are independent of telomerase inhibition or telomere shortening. [Cancer Res 2007;67(3):1121-9]

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“…It has been proposed that shortened telomeres in mitotic (dividing) cells may be responsible for some of the changes we associate with normal aging 4,9,10,33. The strongest correlation of the role of short telomeres in human physiology involves patients with aplastic anemia42 (with mutations in the hTERT gene) and patients with dyskeratosis congenita (with mutations in the hTR gene or a protein associated with hTR, dyskerin) 43–48. In both of these human disorders, there is progressive bone marrow failure that directly correlates with short telomeres.…”

Section: Telomere Hypothesis Of Aging and Cancermentioning

confidence: 99%

Use of Telomerase to Create Bioengineered Tissues

Shay

2005

Annals of the New York Academy of Sciences

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Telomeres are repetitive DNA (TTAGGG) elements at the ends of chromosomes. Telomerase is a ribonucleoprotein complex that catalyzes the addition of telomeric sequences to the ends of chromosomes. The catalytic protein component of telomerase (hTERT) is expressed only in specific germ line cells, proliferative stem cells of renewal tissues, and cancer cells. The expression of hTERT in normal cells reconstitutes telomerase activity and circumvents the induction of senescence. Telomeres shorten with each cell division, eventually leading to senescence (aging), due to incomplete lagging DNA strand synthesis and end-processing events, and because telomerase activity is not detected in most somatic tissues. There are specific tissues and locations in which replicative senescence likely contributes to the decline in human physiological function with increased age and with chronic illnesses. While expressing hTERT in cells results in the maintenance of telomere length and greatly extended life span, blocking replicative aging systemically would be predicted to increase the potential for tumor formation. However, there are many situations in which the transient rejuvenation of cells could be beneficial. Ectopic expression of hTERT has been shown to immortalize human skin keratinocytes, dermal fibroblasts, muscle satellite (stem), and vascular endothelial, myometrial, retinal-pigmented, and breast epithelial cells. In addition, human bronchial, corneal and skin cells expressing hTERT can be used to form organotypic (3D) cultures (bioengineered tissues) that express differentiation-specific proteins, demonstrating that hTERT by itself does not alter normal physiology. The production of hTERT-engineered tissues offers the possibility of producing tissues to treat a variety of chronic diseases and age-related medical conditions that are due to telomere-based replicative senescence.

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Telomeres in dyskeratosis congenita

Abstract: A new study shows that 'anticipation' occurs in the autosomal dominant form of dyskeratosis congenita and is due to inheritance of short telomeres and mutations in TERC (encoding telomerase RNA).

Cited by 35 publications

References 14 publications

Hallmarks of telomeres in ageing research

Hallmarks of telomeres in ageing research

Antiadhesive Effects of GRN163L—An Oligonucleotide N3′→P5′ Thio-Phosphoramidate Targeting Telomerase

Use of Telomerase to Create Bioengineered Tissues

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