Dyskeratosis congenita: a genetic disorder of many faces

Kirwan, Michael; Dokal, Inderjeet

doi:10.1111/j.1399-0004.2007.00923.x

Cited by 209 publications

(184 citation statements)

References 70 publications

(102 reference statements)

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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).…”

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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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DKC1 overexpression associated with prostate cancer progression

et al. 2009

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“…However, there is now a consensus that telomere length correlates to but does not cause aging in most individuals, with immunosenescence being the most tangible correlate (Effros 2007). Exceptions may be a variety of rare premature aging syndromes, such as dyskeratosis congenita (Kirwan and Dokal 2008) and idiopathic pulmonary fibrosis (Blasco 2005), and some cases of liver cirrhosis (Wiemann et al 2002) and myelodysplastic syndromes (Ohyashiki et al 1994), where mutations in telomere maintenance genes have been identified.…”

Section: What Is Not In the Model?mentioning

confidence: 99%

The Szilard Hypothesis on the Nature of Aging Revisited

et al. 2009

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This year marks the 50th anniversary of a nearly forgotten hypothesis on aging by Leo Szilard, best known for his pioneering work in nuclear physics, his participation in the Manhattan Project during World War II, his opposition to the nuclear arms race in the postwar era, and his pioneering ideas in biology. Given a specific set of assumptions, Szilard hypothesized that the major reason for the phenomenon of aging was aging hits, e.g., by ionizing radiation, to the gene-bearing chromosomes and presented a mathematical target-hit model enabling the calculation of the average and maximum life span of a species, as well as the influence of increased exposure to DNA-damaging factors on life expectancy. While many new findings have cast doubt on the specific features of the model, this was the first serious effort to posit accumulated genetic damage as a cause of senescence. Here, we review Szilard's assumptions in the light of current knowledge on aging and reassess his mathematical model in an attempt to reach a conclusion on the relevance of Szilard's aging hypothesis today.

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confidence: 99%

“…Telomerase is a ribonucleoprotein complex, consisting of human transcriptase reverse transcriptase (hTERT), proteins (hTP1), and RNA template for telomeric DNA synthesis (hTERC) [3]; this complex synthesizes telomeres and stabilizes their length. Mutations in any of these components may result in a rare bone marrow failure syndrome known as dyskeratosis congenita [4].Telomerase activity was reported to be low in normal human somatic cells [3]. Proliferating cells become senescent when telomeres are short and when there is no telomerase activity.…”

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Fluorescence in situ hybridization analysis of the hTERC region in acute myeloid leukemia patients

Özer¹,

Balci²,

Yılmaz³

et al. 2011

Turk J Hematol

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Objective: The telomerase RNA component (hTERC) gene is located at 3q26. Increased hTERC gene expression has been frequently observed and amplification was shown using fluorescence in situ hybridization (FISH) in different cancers. The aim of this study was to determine whether hTERC gene amplification is detectable by FISH in acute myeloid leukemia (AML) cells. Material and Methods: FISH and karyotype results at the time of diagnosis of 23 adult AML patients were retrospectively evaluated. Additionally, fixed cells were hybridized with an hTERC region-specific FISH probe to determine gene amplification. Results: Ten of the 23 patients had a normal karyotype and 6 had an abnormal karyotype. hTERC region amplification was not observed in any of the patients. Conclusion: Although it was reported that hTERC gene amplification may partially contribute to increased telomerase expression and activity in leukemic cells, it is not possible to make such a conclusion based on the results of the this study, as hTERC amplification was not observed in the study group. This suggests that increased telomerase activity via gene amplification in the development of AML may not be as important a factor as it is in solid tumors. (Turk J Hematol 2011; 28: 103-6) IntroductionAcute myeloid leukemia (AML) originates from myeloid cells. The disease is characterized by rapid proliferation of abnormal cells, which accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common form of acute leukemia in adults and its incidence increases with age [1]. Morphological, cytochemical, immunophenotypic, cytogenetic, and molecular features of the blasts are important factors in the classification of AML patients [2].Telomeres, located at the ends of chromosomes, determine the replication capacity of cells. They shorten during each cell division and it is generally thought that telomere length serves as a clock for cells. Telomerase is a ribonucleoprotein complex, consisting of human transcriptase reverse transcriptase (hTERT), proteins (hTP1), and RNA template for telomeric DNA synthesis (hTERC) [3]; this complex synthesizes telomeres and stabilizes their length. Mutations in any of these components may result in a rare bone marrow failure syndrome known as dyskeratosis congenita [4].Telomerase activity was reported to be low in normal human somatic cells [3]. Proliferating cells become senescent when telomeres are short and when there is no telomerase activity. Cancer cells are known to overcome this senescence pathway and become immortalized. Immortalization is almost always accompanied by expression of telomerase, which is most likely necessary for the continued growth of cancer cells. Telomerase is activated in most malignant tumours, but is usually inactive in normal somatic cells [3]. Despite the questionable role of telomerase reactivation in cell immortalization and carcinogenesis, telomerase may serve as a diagnostic marker for tumor development [5]. Several studies have shown tha...

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Dyskeratosis congenita: a genetic disorder of many faces

Cited by 209 publications

References 70 publications

DKC1 overexpression associated with prostate cancer progression

DKC1 overexpression associated with prostate cancer progression

The Szilard Hypothesis on the Nature of Aging Revisited

Fluorescence in situ hybridization analysis of the hTERC region in acute myeloid leukemia patients

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