Short telomeres on human chromosome 17p. Nat Genet 18: 76-80

Terry Fox Laboratory for Hematology/Oncology, British Columbia Cancer Research Centre, Vancouver, Canada.
Nature Genetics (Impact Factor: 29.35). 02/1998; 18(1):76-80. DOI: 10.1038/ng0198-018
Source: PubMed


Human chromosomes terminate in a series of T2AG3 repeats, which, together with associated proteins, are essential for chromosome stability. In somatic cells, these sequences are known to be gradually lost through successive cells divisions; however, information about changes on specific chromosomes is not available. Individual telomeres could mediate important biological effects as was shown in yeast, in which loss of a single telomere results in cell-cycle arrest and chromosome loss. We now demonstrate by quantitative fluorescence in situ hybridization (Q-FISH; ref. 7) that the number of T2AG3 repeats on specific chromosome arms is very similar in different tissues from the same donor and varies only to some extent between donors. In all sixteen individuals studied, telomeres on chromosome 17p were shorter than the median telomere length--a finding confirmed by analysis of terminal restriction fragments from sorted chromosomes. These observations provide evidence of chromosome-specific factors regulating the number of T2AG3 repeats in individual telomeres and raise the possibility that the relatively short telomeres on chromosome 17p contribute to the frequent loss of 17p alleles in human cancers.

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    • "FISH is a flexible technique that has driven the further development of other cytogenetic techniques. There are multiple approaches using FISH-based methods for different applications, e.g., reverse-FISH (Carter et al., 1992), fiber-FISH (Florijn et al., 1995; Heiskanen et al., 1995), (M-FISH multicolor FISH) (Speicher et al., 1996), SKY (spectral karyotyping FISH) (Schröck et al., 1996), flow-FISH (Rufer et al., 1998), Q-FISH (quantitative FISH) (Martens et al., 1998), COBRA-FISH (combined binary ratio labeling FISH) (Tanke et al., 1999), cenM-FISH (centromere-specific M-FISH) (Nietzel et al., 2001), pod-FISH (parental origin determination FISH) (Weise et al., 2008), (heterochromatin-M-FISH) (Bucksch et al., 2012) and other modified FISH approaches. If modified, several FISH techniques can also be applied to interphase cells (interphase FISH) (Vorsanova et al., 2010), which confers the advantages of FISH for the visualization of DNA probes in interphase nuclei (Cremer et al., 1986). "
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    ABSTRACT: The field of cytogenetics has focused on studying the number, structure, function and origin of chromosomal abnormalities and the evolution of chromosomes. The development of fluorescent molecules that either directly or via an intermediate molecule bind to DNA has led to the development of fluorescent in situ hybridization (FISH), a technology linking cytogenetics to molecular genetics. This technique has a wide range of applications that increased the dimension of chromosome analysis. The field of cytogenetics is particularly important for medical diagnostics and research as well as for gene ordering and mapping. Furthermore, the increased application of molecular biology techniques, such as array-based technologies, has led to improved resolution, extending the recognized range of microdeletion/microduplication syndromes and genomic disorders. In adopting these newly expanded methods, cytogeneticists have used a range of technologies to study the association between visible chromosome rearrangements and defects at the single nucleotide level. Overall, molecular cytogenetic techniques offer a remarkable number of potential applications, ranging from physical mapping to clinical and evolutionary studies, making a powerful and informative complement to other molecular and genomic approaches. This manuscript does not present a detailed history of the development of molecular cytogenetics; however, references to historical reviews and experiments have been provided whenever possible. Herein, the basic principles of molecular cytogenetics, the technologies used to identify chromosomal rearrangements and copy number changes, and the applications for cytogenetics in biomedical diagnosis and research are presented and discussed.
    Preview · Article · Mar 2014 · Genetics and Molecular Biology
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    • "The median length of the virus-associated telomere was compared with the length of XpYp, 12q and 17 p telomeres. In 50% (8/16) of the LCLs, the CI-HHV-6-associated telomere was the shortest measured (Figure 3B, Supplementary Figure S3A) (9,38), even compared with the 17 p telomere that has been reported as often being the shortest (36,39). Corresponding analysis of blood DNA samples from 24 carriers (21 CI-HHV-6B from the Orkney Complex Disease Study study, and 3 CI-HHV-6 A siblings in a British family) again showed that the virus-associated telomere was most often the shortest [42% (10/24); Figure 3B and Supplementary Figure S3B], indicating that short virus-associated telomeres do not arise from the establishment or propagation of LCLs. "
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    ABSTRACT: Linear chromosomes are stabilized by telomeres, but the presence of short dysfunctional telomeres triggers cellular senescence in human somatic tissues, thus contributing to ageing. Approximately 1% of the population inherits a chromosomally integrated copy of human herpesvirus 6 (CI-HHV-6), but the consequences of integration for the virus and for the telomere with the insertion are unknown. Here we show that the telomere on the distal end of the integrated virus is frequently the shortest measured in somatic cells but not the germline. The telomere carrying the CI-HHV-6 is also prone to truncations that result in the formation of a short telomere at a novel location within the viral genome. We detected extra-chromosomal circular HHV-6 molecules, some surprisingly comprising the entire viral genome with a single fully reconstituted direct repeat region (DR) with both terminal cleavage and packaging elements (PAC1 and PAC2). Truncated CI-HHV-6 and extra-chromosomal circular molecules are likely reciprocal products that arise through excision of a telomere-loop (t-loop) formed within the CI-HHV-6 genome. In summary, we show that the CI-HHV-6 genome disrupts stability of the associated telomere and this facilitates the release of viral sequences as circular molecules, some of which have the potential to become fully functioning viruses.
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    • "To validate the use of Q-FISH for measurements of the length of telomeric repeats we hybridized five cell lines with different size of TTAGGG repeat sequences with the Cy3-PNA telomeric probe. Telomere fluorescence units (TFU) are converted into kilobase (Kb) by external calibration with the L5178Y-S and L5178Y-R murine lymphoma cell lines, MEF murine embryonic fibroblast cell line, MCF7 and HeLa human tumor cell lines with known TL of 10.2 Kb, 79.7 kb, 47 Kb, 4.07 Kb and 3.44 Kb, respectively [42]. For each cell line the median fluorescence intensity was directly proportional to the size of the TTAGGG repeats sequences and the resulting calibration line was used to express telomere fluorescence in TFU with corresponding Kb of TTAGGG repeats. "
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a complex multi-factorial disease with life-threatening complications. AAA is typically asymptomatic and its rupture is associated with high mortality rate. Both environmental and genetic risk factors are involved in AAA pathogenesis. Aim of this study was to investigate telomere length (TL) and oxidative DNA damage in paired blood lymphocytes, aortic endothelial cells (EC), vascular smooth muscle cells (VSMC), and epidermal cells from patients with AAA in comparison with matched controls. TL was assessed using a modification of quantitative (Q)-FISH in combination with immunofluorescence for CD31 or α-smooth muscle actin to detect EC and VSMC, respectively. Oxidative DNA damage was investigated by immunofluorescence staining for 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG). Telomeres were found to be significantly shortened in EC, VSMC, keratinocytes and blood lymphocytes from AAA patients compared to matched controls. 8-oxo-dG immunoreactivity, indicative of oxidative DNA damage, was detected at higher levels in all of the above cell types from AAA patients compared to matched controls. Increased DNA double strand breaks were detected in AAA patients vs controls by nuclear staining for γ-H2AX histone. There was statistically significant inverse correlation between TL and accumulation of oxidative DNA damage in blood lymphocytes from AAA patients. This study shows for the first time that EC and VSMC from AAA have shortened telomeres and oxidative DNA damage. Similar findings were obtained with circulating lymphocytes and keratinocytes, indicating the systemic nature of the disease. Potential translational implications of these findings are discussed.
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