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Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer  [PDF]
Beatriz Martinez-Delgado equal contributor ,Kira Yanowsky equal contributor,Lucia Inglada-Perez,Samuel Domingo,Miguel Urioste,Ana Osorio,Javier Benitez
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002182
Abstract: There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.
Diminished Telomeric 3′ Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome  [PDF]
Noa Lamm, Elly Ordan, Rotem Shponkin, Carmelit Richler, Memet Aker, Yehuda Tzfati
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005666
Abstract: Background Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency. Methodology/Principal Findings We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3′ overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types. Conclusions/Significance Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.
Telomere Shortening Impairs Regeneration of the Olfactory Epithelium in Response to Injury but Not Under Homeostatic Conditions  [PDF]
Masami Watabe-Rudolph,Yvonne Begus-Nahrmann,André Lechel,Harshvardhan Rolyan,Marc-Oliver Scheithauer,Gerhard Rettinger,Dietmar Rudolf Thal,Karl Lenhard Rudolph
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0027801
Abstract: Atrophy of the olfactory epithelium (OE) associated with impaired olfaction and dry nose represents one of the most common phenotypes of human aging. Impairment in regeneration of a functional olfactory epithelium can also occur in response to injury due to infection or nasal surgery. These complications occur more frequently in aged patients. Although age is the most unifying risk factor for atrophic changes and functional decline of the olfactory epithelium, little is known about molecular mechanisms that could influence maintenance and repair of the olfactory epithelium. Here, we analyzed the influence of telomere shortening (a basic mechanism of cellular aging) on homeostasis and regenerative reserve in response to chemical induced injury of the OE in late generation telomere knockout mice (G3 mTerc?/?) with short telomeres compared to wild type mice (mTerc+/+) with long telomeres. The study revealed no significant influence of telomere shortening on homeostatic maintenance of the OE during mouse aging. In contrast, the regenerative response to chemical induced injury of the OE was significantly impaired in G3 mTerc?/? mice compared to mTerc+/+ mice. Seven days after chemical induced damage, G3 mTerc?/? mice exhibited significantly enlarged areas of persisting atrophy compared to mTerc+/+ mice (p = 0.031). Telomere dysfunction was associated with impairments in cell proliferation in the regenerating epithelium. Deletion of the cell cycle inhibitor, Cdkn1a (p21) rescued defects in OE regeneration in telomere dysfunctional mice. Together, these data indicate that telomere shortening impairs the regenerative capacity of the OE by impairing cell cycle progression in a p21-dependent manner. These findings could be relevant for the impairment in OE function in elderly people.
Association of telomere instability with senescence of porcine cells  [cached]
Ji Guangzhen,Liu Kai,Okuka Maja,Liu Na
BMC Cell Biology , 2012, DOI: 10.1186/1471-2121-13-36
Abstract: Background Telomeres are essential for the maintenance of genomic stability, and telomere dysfunction leads to cellular senescence, carcinogenesis, aging, and age-related diseases in humans. Pigs have become increasingly important large animal models for preclinical tests and study of human diseases, and also may provide xeno-transplantation sources. Thus far, Southern blot analysis has been used to estimate average telomere lengths in pigs. Telomere quantitative fluorescence in situ hybridization (Q-FISH), however, can reveal status of individual telomeres in fewer cells, in addition to quantifying relative telomere lengths, and has been commonly used for study of telomere function of mouse and human cells. We attempted to investigate telomere characteristics of porcine cells using telomere Q-FISH method. Results The average telomere lengths in porcine cells measured by Q-FISH correlated with those of quantitative real-time PCR method (qPCR) or telomere restriction fragments (TRFs) by Southern blot analysis. Unexpectedly, we found that porcine cells exhibited high incidence of telomere doublets revealed by Q-FISH method, coincided with increased frequency of cellular senescence. Also, telomeres shortened during subculture of various porcine primary cell types. Interestingly, the high frequency of porcine telomere doublets and telomere loss was associated with telomere dysfunction-induced foci (TIFs). The incidence of TIFs, telomere doublets and telomere loss increased with telomere shortening and cellular senescence during subculture. Conclusion Q-FISH method using telomere PNA probe is particularly useful for characterization of porcine telomeres. Porcine cells exhibit high frequency of telomere instability and are susceptible to telomere damage and replicative senescence.
Rapid telomere motions in live human cells analyzed by highly time-resolved microscopy
Xueying Wang, Zvi Kam, Peter M Carlton, Lifeng Xu, John W Sedat, Elizabeth H Blackburn
Epigenetics & Chromatin , 2008, DOI: 10.1186/1756-8935-1-4
Abstract: The motility of individual telomeres within the same cancer cell nucleus was widely heterogeneous. One class of internal heterochromatic regions of chromosomes analyzed moved more uniformly and showed less motion and heterogeneity than telomeres. The single telomere analyses in cancer cells revealed that shorter telomeres showed more motion, and the more rapid telomere motions were energy dependent. Experimentally increasing bulk telomere length dampened telomere motion. In contrast, telomere uncapping, but not a DNA damaging agent, methyl methanesulfonate, significantly increased telomere motion.New methods for seconds-scale, four-dimensional, live cell microscopic imaging and data analysis, allowing systematic tracking of individual telomeres in live cells, have defined a previously undescribed form of telomere behavior in human cells, in which the degree of telomere motion was dependent upon telomere length and functionality.Telomeres, essential for protecting chromosome ends [1-3], consist of tandem telomeric DNA repeats bound by multiple proteins that collectively 'cap' the telomere (reviewed in [4]). A minimum length of telomeric repeats is necessary to support this protective function. Telomeric repeats are replenished by the cellular ribonucleoprotein enzyme, telomerase [2,5]. Most human cancer cells have high telomerase activity. In contrast, normal human cells have naturally limited levels of telomerase that can lead to telomere shortening over time. Many aspects of telomeres remain incompletely understood, especially their dynamic properties and behavior over time. At one extreme, over the decades of human lifespan, telomeres generally shorten, with rates and extents that have been associated with disease progression and risk [6-9]. Here we report new findings on telomere behavior at the other end of the timescale spectrum: the dynamics of individual human telomeres in living cells analyzed at 1-second time resolution.The dynamics of the nuclear contents
Defective Artemis causes mild telomere dysfunction
Hemad Yasaei, Predrag Slijepcevic
Genome Integrity , 2010, DOI: 10.1186/2041-9414-1-3
Abstract: We observed significantly elevated frequencies of telomeric fusions in two primary fibroblast cell lines established from Artemis defective patients relative to the control cell line. The frequencies of telomeric fusions increased after exposure of Artemis defective cells to ionizing radiation. Furthermore, we observed increased incidence of DNA damage at telomeres in Artemis defective cells that underwent more than 32 population doublings using the TIF (Telomere dysfunction Induced Foci) assay. We have also inhibited the expression levels of DNA-PKcs in Artemis defective cell lines by either using synthetic inhibitor (IC86621) or RNAi and observed their greater sensitivity to telomere dysfunction relative to control cells.These results suggest that defective Artemis causes a mild telomere dysfunction phenotype in human cell lines.There is increasing evidence that the maintenance of telomeres, physical ends of chromosomes, and DNA damage response mechanisms are interlinked. The first observation of a telomere dysfunction phenotype in a DNA damage response defective environment was reported in the case of Ataxia telangiectasia (AT) cells. The telomere dysfunction phenotype in cells from AT patients or ATM (AT mutated) defective mice ranges from accelerated telomere shortening to end-to-end chromosome fusions and extra-chromosomal telomeric fragments [1,2]. Following the observation of telomere dysfunction associated with the ATM defect, a number of DNA damage response factors have been shown to affect telomere maintenance. Most notably, proteins involved in the repair of DNA double strand breaks (DSBs) either by Non-Homologous End Joining (NHEJ) or homologous recombination (HR) including Ku, DNA-PKcs, RAD54, RAD51D and BRCA1 if dysfunctional, will cause a severe telomere dysfunction phenotype [3-6]. So far, at least 17 DNA damage response proteins have been shown to affect telomere maintenance [7]. It is not yet clear as to why the interplay between telomere maintena
Mesenchymal stem cells with high telomerase expression do not actively restore their chromosome arm specific telomere length pattern after exposure to ionizing radiation
Jesper Graakjaer, Rikke Christensen, Steen Kolvraa, Nedime Serakinci
BMC Molecular Biology , 2007, DOI: 10.1186/1471-2199-8-49
Abstract: A telomere length pattern was found to exist in primary hMSC's as well as in hMSC-telo1. This pattern is similar to what was previously found in lymphocytes and fibroblasts. The cells were then exposed to a high dose of ionizing radiation. Irradiation caused profound changes in chromosome specific telomere lengths, effectively destroying the telomere length pattern. Following long term culturing after irradiation, a telomere length pattern was found to re-emerge. However, the new telomere length pattern did not resemble the telomere length pattern observed before irradiation.Our findings indicate that a telomere length pattern does exist in mesenchymal stem cells and that the pattern is not actively re-established after destruction by irradiation.Telomeres consist of repetitive non-coding sequences located at the very end of all chromosomes in higher organisms [1]. The telomeres form a loop structure which in collaboration with a number of specific telomere associated proteins, protects chromosome ends from degradation and chromosome fusion [2]. Telomeres have been found to shorten with each cell division due to a process called the "end replication problem" and possibly due to acquired oxidative damage [3,4]. This gradual shortening of the telomeres during life continues until the telomeres reach a certain length, at which stage the presence of critically short telomeres triggers a p53/Rb mediated senescence pathway. Cell culture experiments show that due to this limitation of division potential, normal human cells can only divide 50–100 times [5]. It has been proposed that this limitation of division potential may limit the ultimate lifespan of human individuals [6]. An increasing body of evidence suggests that the shortest telomere in a cell is responsible for triggering the p53/Rb pathway. It is therefore highly relevant that we and others have found that telomere lengths are not randomly distributed at chromosome ends [7,8]. In a series of investigations we hav
The Individual Blood Cell Telomere Attrition Rate Is Telomere Length Dependent  [PDF]
Katarina Nordfj?ll,Ulrika Svenson,Karl-Fredrik Norrback,Rolf Adolfsson,Per Lenner,G?ran Roos
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000375
Abstract: Age-associated telomere shortening is a well documented feature of peripheral blood cells in human population studies, but it is not known to what extent these data can be transferred to the individual level. Telomere length (TL) in two blood samples taken at ~10 years interval from 959 individuals was investigated using real-time PCR. TL was also measured in 13 families from a multigenerational cohort. As expected, we found an age-related decline in TL over time (r = –0.164, P<0.001, n = 959). However, approximately one-third of the individuals exhibited a stable or increased TL over a decade. The individual telomere attrition rate was inversely correlated with initial TL at a highly significant level (r = –0.752, P<0.001), indicating that the attrition rate was most pronounced in individuals with long telomeres at baseline. In accordance, the age-associated telomere attrition rate was more prominent in families with members displaying longer telomeres at a young age (r = –0.691, P<0.001). Abnormal blood TL has been reported at diagnosis of various malignancies, but in the present study there was no association between individual telomere attrition rate or prediagnostic TL and later tumor development. The collected data strongly suggest a TL maintenance mechanism acting in vivo, providing protection of short telomeres as previously demonstrated in vitro. Our findings might challenge the hypothesis that individual TL can predict possible life span or later tumor development.
Saccharomyces cerevisiae as a Model to Study Replicative Senescence Triggered by Telomere Shortening  [PDF]
M. Teresa Teixeira
Frontiers in Oncology , 2013, DOI: 10.3389/fonc.2013.00101
Abstract: In many somatic human tissues, telomeres shorten progressively because of the DNA-end replication problem. Consequently, cells cease to proliferate and are maintained in a metabolically viable state called replicative senescence. These cells are characterized by an activation of DNA damage checkpoints stemming from eroded telomeres, which are bypassed in many cancer cells. Hence, replicative senescence has been considered one of the most potent tumor suppressor pathways. However, the mechanism through which short telomeres trigger this cellular response is far from being understood. When telomerase is removed experimentally in Saccharomyces cerevisiae, telomere shortening also results in a gradual arrest of population growth, suggesting that replicative senescence also occurs in this unicellular eukaryote. In this review, we present the key steps that have contributed to the understanding of the mechanisms underlying the establishment of replicative senescence in budding yeast. As in mammals, signals stemming from short telomeres activate the DNA damage checkpoints, suggesting that the early cellular response to the shortest telomere(s) is conserved in evolution. Yet closer analysis reveals a complex picture in which the apparent single checkpoint response may result from a variety of telomeric alterations expressed in the absence of telomerase. Accordingly, the DNA replication of eroding telomeres appears as a critical challenge for senescing budding yeast cells and the easy manipulation of S. cerevisiae is providing insights into the way short telomeres are integrated into their chromatin and nuclear environments. Finally, the loss of telomerase in budding yeast triggers a more general metabolic alteration that remains largely unexplored. Thus, telomerase-deficient S. cerevisiae cells may have more common points than anticipated with somatic cells, in which telomerase depletion is naturally programed, thus potentially inspiring investigations in mammalian cells.
The Effect of Pro-Inflammatory Conditioning and/or High Glucose on Telomere Shortening of Aging Fibroblasts  [PDF]
Klelia D. Salpea, Cecilia G. Maubaret, Annegret Kathagen, Gie Ken-Dror, Derek W. Gilroy, Steve E. Humphries
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073756
Abstract: Cardiovascular disease and diabetes have been linked to shorter telomeres, but it is not yet clear which risk factors contribute to shorter telomeres in patients. Our aim was to examine whether pro-inflammatory conditioning, in combination or not with high glucose, result in a higher rate of telomere shortening during in vitro cellular ageing. Human fibroblasts from four donors were cultured for 90 days in: 1) medium lacking ascorbic acid only, 2) 10 mM buthionine sulphoximine (BSO) (pro-oxidant), 3) 25 mM D-glucose, 4) 1 ng/ml IL1B and 5) 25 mM D-glucose+1 ng/ml IL1B. Telomere length was measured with qPCR and intracellular reactive oxygen species (ROS) content and cell death with flow cytometry. Cultures treated with high glucose and BSO displayed a significantly lower growth rate, and cultures treated with IL1B showed a trend towards a higher growth rate, compared to the control [Glucose:0.14 PD/day, p<0.001, BSO: 0.11 PD/day, p = 0.006 and IL1B: 0.19 PD/day, p = 0.093 vs. Control:0.16 PD/day]. Telomere shortening with time was significantly accelerated in cultures treated with IL1B compared to the control [IL1B:?0.8%/day (95%CI:?1.1, ?0.5) vs. Control:?0.6%/day (95%CI:?0.8, ?0.3), p = 0.012]. The hastening of telomere shortening by IL1B was only in part attenuated after adjustment for the number of cell divisions [IL1B:?4.1%/PD (95%CI:?5.7, ?2.4) vs. Control:?2.5%/PD (95%CI:?4.4, ?0.7), p = 0.067]. The intracellular ROS content displayed 69% increase (p = 0.033) in BSO compared to the control. In aging fibroblasts, pro-inflammatory conditioning aggravates the shortening of telomeres, an effect which was only in part driven by increased cell turnover. High glucose alone did not result in greater production of ROS or telomere shortening.
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