Dyskeratosis Congenita - A Disease of Dysfunctional Telomere Maintenance

Mason, Philip J.; Wilson, David B.; Bessler, Monica

doi:10.2174/1566524053586581

Cited by 122 publications

(94 citation statements)

References 61 publications

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“…In this progression, telomere shortening in HSCs is considered to be a risk factor that contributes to the development of chromosomal instability and malignant transformation. In agreement with this hypothesis, telomere shortening in patients with DKC correlates with an increased risk of haematological neoplasia (Mason et al, 2005). Similar to haematopoietic malignancies, several kinds of solid cancers, especially breast and brain cancers (Singh et al, 2003;Al-Hajj and Clarke, 2004), are considered to be generated and/or propagated by CSCs.…”

Section: Cancer Stem Cellsmentioning

confidence: 66%

Telomere and telomerase in stem cells

2007

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Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.

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Section: Cancer Stem Cellsmentioning

confidence: 66%

Telomere and telomerase in stem cells

2007

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“…Familial HNSCC with germline mutations of p16INK4a has been described [12]. Interesting developments have emerged in the genetics of dyskeratosis congenita, in which the various mutations all involve components of the telomerase complex [16]. The primary defect appears to be dysfunction in telomere maintenance.…”

Section: Syndromes Associated With Hnsccmentioning

confidence: 99%

Head and Neck Squamous Cell Carcinoma in the Young: A Spectrum or a Distinct Group? Part 1

Toner

O’Regan²

2009

Head and Neck Pathol

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While most head and neck squamous carcinoma (HNSCC) occurs in older people, an increasing number of young patients are being affected worldwide, with up to 5.5% \40. These are predominantly oral and oropharyngeal cancers. Some patients have heavy exposure to the usual risk factors, but an increasing number do not. Part of this trend appears to be due to rising numbers of HPV associated tonsil carcinoma, particularly in males (smokers and non-smokers).

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“…Dyskerin, also known as Cbf5, is a predominantly nucleolar protein encoded by the DKC1 gene at Xq28 (Mason et al, 2005;Kirwan and Dokal, 2008). As part of a snoRNA ribonucleoprotein complex, dyskerin catalyses the formation of pseudouridine in ribosomal and certain small RNAs (Filipowicz and Pogacic, 2002).…”

mentioning

confidence: 99%

DKC1 overexpression associated with prostate cancer progression

et al. 2009

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BACKGROUND: Dyskerin encoded by the DKC1 gene is a predominantly nucleolar protein essential for the formation of pseudouridine in RNA and the telomerase RNA subunit hTR. Inherited mutations inactivating dyskerin cause dyskeratosis congenita, a syndrome with progeroid features characterised by skin defects and haematopoiesis failure, as well as cancer susceptibility. In this study, we report DKC1 overexpression in prostate cancers. METHODS: Expression of DKC1 was measured by quantitative RT -PCR in prostate cancer tissues in relation to hTR and the proliferation marker MKI67. Effects of dyskerin downregulation on proliferation, apoptosis and senescence of prostate cancer cell lines were determined. RESULTS: DKC1 was significantly overexpressed in prostate cancers, particularly in high-stage and recurring cases, correlating moderately with hTR and MKI67. Dyskerin downregulation in prostate carcinoma cell lines by siRNA diminished cell proliferation, but elicited neither apoptosis nor senescence. Apoptosis induction by TNF-a or tunicamycin was not enhanced. Long-term downregulation led predominantly to cell shrinking and loss of adhesion. INTERPRETATION: DKC1 upregulation in prostate cancers is common and likely to be necessary for extensive tumour growth. The phenotype of prostate carcinoma cell lines after dyskerin downregulation suggests that its most critical function is sustaining protein biosynthesis. Intriguingly, compromised function and overexpression of dyskerin can both contribute to cancer development.

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Dyskeratosis Congenita - A Disease of Dysfunctional Telomere Maintenance

Cited by 122 publications

References 61 publications

Telomere and telomerase in stem cells

Telomere and telomerase in stem cells

Head and Neck Squamous Cell Carcinoma in the Young: A Spectrum or a Distinct Group? Part 1

DKC1 overexpression associated with prostate cancer progression

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