Using in situ hybridisation, we identified interstitial telomeric sequences in seven chromosomal translocations present in normal and in syndromic subjects. Telomeric sequences were also found at the centromeric ends of a 4p and a 4q caused by centric fission of one chromosome 4. We found that rearrangements leading to interstitial telomeric sequences were of three types: (1) termino-terminal rearrangements with fusion of the telomeres of two chromosomes, of which we report one case; (2) rearrangements in which an acentric fragment of one chromosome fuses to the telomere of another chromosome. We describe four cases of Prader-Willi syndrome with the 15q1-qter transposed to the telomeric repeats of different recipient chromosomes; (3) telomere-centromere rearrangements in which telomeric sequences of one chromosome fuse with the centromere of another chromosome. We describe two examples of these rearrangements in which not only telomeric sequences but also remnants of alphoid sequences were found ...
Figure 1. Telomere-specific FISH in prostate adenocarcinomas. A-D, examples of telomere length and cell-to-cell variability in telomere length in malignant and benign prostate tissue from men in the HPFS who were surgically treated for clinically localized prostate cancer. A, this case has strikingly variable telomere signals among the cancer cells. B, this case has extremely short telomere signals and low variability in telomere length from cancer cell to cancer cell. C, this case has weak telomere signals in the CAS cells. D, this case has strong telomere signals in CAS cells. In all of the images, the DNA is stained with DAPI (blue) and telomere DNA is stained with the Cy3-labeled telomere-specific peptide nucleic acid probe (red). Of note, the centromere DNA, stained with the FITC-labeled centromere-specific peptide nucleic acid probe, has been omitted from the image to emphasize the differences in the telomere lengths. In all panels, the asterisks highlight the cancer cells and the arrows ...
Previously, we observed that heterochromatic 4 and Y chromosomes that had experienced breakage in the male germline were frequently transmitted to progeny. Their behavior suggested that they carried functional telomeres. Here we show that efficient healing by de novo telomere addition is not unique to heterochromatic breaks. ...
Telomeres are the outermost parts of linear chromosomes. They consist of tandemly repeated non-coding short nucleotide sequences (TTAGGG in all vertebrates), in humans spanning over the last 2 to 15 kilobase pairs of the chromosome. Due to the end-replication problem, telomeres shorten with each cellular division. A critically short telomere will trigger the cell to enter a state of cellular senescence or to apoptose. The rate of telomere shortening can be accelerated by factors such as oxidative stress and inflammation. Taken together, this contributed to making telomere length a candidate biomarker of health and aging. Studies have shown that leukocyte telomere length progressively shortens with age, and that it independent of age is associated with age-related morbidity, lifestyle factors, and mortality. This thesis was aimed at exploring the relationships of leukocyte telomere length with various functional and structural attributes of the brain.. In Paper I, telomere length was shown to be ...
Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere ...
The SNP rs398652 on 14q21 and several other promising genetic variants were associated in our GWAS with telomere length in leukocytes. We then found that rs398652 was also associated with reduced bladder cancer risk. This SNP is located within the region of 14q that has a high linkage with leukocyte telomere length and is fewer than 450 kb from a microsatellite marker (D14S285) shown to have a very high logarithm (base 10) of odds (LOD) of approximately 3.5 for linkage with telomere length in a previous genetic linkage analysis (27). Furthermore, our mediation analysis to dissect the relationship between rs398652, telomere length, and bladder cancer risk suggests that the association of this SNP with bladder cancer is partially mediated by telomere length.. Telomere shortening and telomerase activation are critical early events of tumorigenesis. Results from a number of epidemiologic studies suggest that shorter telomere length in leukocytes is associated with increased cancer risks for several ...
Human telomeres can be maintained by the enzyme telomerase, which catalyses the addition of telomere repeats, or by the Alternative Lengthening of Telomeres (ALT) mechanism, which is recombination based. Recently, knockout mouse cell lines have indicated that epigenetic modifications associated with telomeric and subtelomeric chromatin, including DNA methylation, Histone 3 Lysine 9 (H31K9) trimethylation and Histone 4 Lysine 20 (H4K20) trimethylation, play an important role in influencing the choice of telomere maintenance mechanism. In this thesis, the levels of these modifications were studied in telomeric chromatin and in the telomere adjacent chromatin of the short arm of the human sex chromosomes (XpYp) in a panel of six human cell lines utilising different telomere maintenance mechanisms. In marked contrast to mouse models, no relationship was found between the level of any of these modifications and telomere maintenance pathway. This may indicate that the role such marks play at telomeres ...
The protective caps on chromosome ends - known as telomeres - consist of DNA and associated proteins that are essential for chromosome integrity. A fundamental part of ensuring proper telomere function is maintaining adequate length of the telomeric DNA tract. Telomeric repeat sequences are synthesized by the telomerase reverse transcriptase, and, as such, telomerase is a central player in the maintenance of steady-state telomere length. Evidence from both yeast and mammals suggests that telomere-associated proteins positively or negatively control access of telomerase to the chromosome terminus. In yeast, positive regulation of telomerase access appears to be achieved through recruitment of the enzyme by the end-binding protein Cdc13p. In contrast, duplex-DNA-binding proteins assembled along the telomeric tract exert a feedback system that negatively modulates telomere length by limiting the action of telomerase. In mammalian cells, and perhaps also in yeast, binding of these proteins probably ...
The CDC13 gene has previously been implicated in the maintenance of telomere integrity in Saccharomyces cerevisiae. With the use of two classes of mutations, here it is shown that CDC13 has two discrete roles at the telomere. The cdc13-2est mutation perturbs a function required in vivo for telomerase regulation but not in vitro for enzyme activity, whereas cdc13-1ts defines a separate essential role at the telomere. In vitro, purified Cdc13p binds to single-strand yeast telomeric DNA. Therefore, Cdc13p is a telomere-binding protein required to protect the telomere and mediate access of telomerase to the chromosomal terminus.. ...
Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular
Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular
Telomeres are the ends of eukaryotic chromosomes, consisting of consecutive short repeats that protect chromosome ends from degradation. Telomeres shorten with each cell division, leading to replicative cell senescence. Deregulation of telomere length homeostasis is associated with the development of various age-related diseases and cancers. A number of experimental techniques exist for telomere length measurement; however, until recently, the absence of tools for extracting telomere lengths...
Newborn telomere length sets telomere length for later life. At birth, telomere length is highly variable among newborns and the environmental factors during in utero life for this observation remain largely unidentified. Obesity during pregnancy might reflect an adverse nutritional status affecting pregnancy and offspring outcomes, but the association of maternal pre-pregnancy body mass index (BMI) with newborn telomere length, as a mechanism of maternal obesity, on the next generation has not been addressed. Average relative telomere lengths were measured in cord blood (n = 743) and placental tissue (n = 702) samples using a quantitative real-time PCR method from newborns from the ENVIRONAGE birth cohort in Belgium. By using univariate and multivariable adjusted linear regression models we addressed the associations between pre-pregnancy BMI and cord blood and placental telomere lengths. Maternal age was 29.1 years (range, 17-44) and mean (SD) pre-pregnancy BMI was 24.1 (4.1) kg/m2. Decline in newborn
Almost 12 years ago, an evolutionary theory based on intergenerational telomere erosion was introduced [8] and was widely covered by the press [11, 12]. In 2011, based on published data on human telomere length inheritance, I refined my theoretical framework and located the source of human intergenerational telomere erosion in the female germline [6, 7, 10]. According to this model, telomeres in the testes of elderly males are longer than those in young males because the seniors are members of a previous generation (=birth-cohort effect) and therefore skipped, on average, one female-based intergenerational telomere loss. In 2014, I further developed the model of telomere-driven macroevolution and presented a complete biological framework for the old European model of saltatory evolution of nonadaptive characters [6].. In agreement with this theoretical model, a high-profile study, published in the August issue of Aging Cell in 2015, finally confirmed the long-awaited birth-cohort effect on ...
Telomere length analysis of donor-derived bone marrow cells (Fig. 3) and HSCs (Fig. 4) shows substantial telomere shortening during serial HSC transplantation. The difference in mean TRF length (ΔTRF) of bone marrow cells after one round of HSC transplantation is ∼1.5 kb (Fig. 3 B). This agrees reasonably well with the predicted reduction in telomere size assuming that ΔTRF is mainly due to the minimum number of extra population doublings (∼12-13) required for expansion of the fraction of the transplanted HSC population which engraft to the size of the HSC pool in adult mice (∼3-5 × 104 cells; references 3, 4), and that the rate of telomere shortening during division of the transplanted HSCs is 50-100 bp per population doubling, as observed for other mouse cells 14,39,40. However, the extent of telomere shortening during the second round of HSC transplantation (ΔTRF ≈ 5.5 kb) is considerably greater than ΔTRF during the first round of transplantation (Fig. 3). One possible ...
The results described in this study provided evidences that SYUIQ5, a Gquadruplex ligand, potently inhibited the proliferation and induced telomere DNA damage and autophagy in CNE2 and HeLa cancer cells in vitro. TRF2 delocalized from telomeres after SYUIQ5 treatment and was further degraded by proteasomes. In addition, overexpression of TRF2 prevented SYUIQ5-mediated cell death. ATM was also activated and involved in SYUIQ-5-induced telomere DNA damage response and autophagy. Furthermore, ATG5 knockdown attenuated the cytotoxicity of SYUIQ-5 in CNE2 and HeLa cells.. Telomeres are capable of forming guanine quadruplex (G4) structures on the G-rich strand, and the ligands that interact with G-quadruplex are recognized as promising anticancer agents by interfering with telomere conformation and telomere elongation. These compounds were first evaluated as telomerase inhibitors and induced telomere shortening and senescence. Recently, it was observed that G-quadruplex ligands induced a short-term ...
Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity
4. The Curious Case of Skeletal Muscle Telomere Biology in Humans Skeletal muscle has unique telomere biology when compared to other tissues. Skeletal muscle consists of a syncytium of multinucleated muscle fibers that are postmitotic; thus, telomere length should remain stable in this population of nuclei, with the rare exception of DNA damaging stimuli [89]. In addition to myonuclei, single-nucleated populations of cells, of which the best described are satellite cells, also populate skeletal muscle [90]. Satellite cells are muscle precursor cells (i.e., adult stem cells) that are quiescent unless induced to divide by external stressors, such as contraction-induced or injury-induced muscle damage [90]. When induced to divide, satellite cells divide asymmetrically, with one daughter cell incorporating into the damaged muscle fiber and the other daughter cell returning to replenish the satellite cell pool [90]. Skeletal muscle telomere dogma states that when a muscle precursor cell is induced to ...
It is not the length of telomeres per se that protects against loss of chromosome end function, but the ability to maintain sufficient length to form a functional telomere cap. Although equilibrium telomere lengths vary dramatically between yeast, mice and humans, they share a dosage-sensitive balance between telomere loss and replenishment. In heterozygous mTert mice that have been bred for many generations, we propose that initial telomere attrition followed by eventual recovery reflects such a length-dependent equilibrium. In S. cerevisiae and humans, long telomeres inhibit telomerase access owing to cis-inhibition by telomere-bound factors such as Rif1/Rif2 and TRF1/TRF2, respectively (Smogorzewska and de Lange, 2004; Hug and Lingner, 2006). Once telomeres become short, the dosage of telomere-bound factors is reduced, leading to loss of cis-inhibition and a switch to a telomerase-extendible state (Smogorzewska and de Lange, 2004; Hug and Lingner, 2006). Upon telomere shortening, murine cells ...
We measured the effects of long-term NRTI and NNRTI exposure on telomere length maintenance using the HT29 human colorectal adenocarcinoma cell model (Table 2). HT29 has robust telomerase activities, as measured by the PCR-based telomerase activity assay [31]. HT29 cells were treated with a minimum of two concentrations of NRTIs or NNRTIs. Cell proliferation and growth rate was monitored continuously. Long-term treatment of HT29 cells with AZT is known to cause telomere length attrition [9,10,11,13]. Using the terminal restriction fragment (TRF) assay, we confirmed substantial inhibitory effects of AZT on telomere length maintenance in HT29 cells (Figure 6A and 6B). Mean telomere length was determined as a weighted average with reference to DNA standards. Figure 7. Continuous treatment of HT29 cells with the adenosine analogs TDF and ddI causes observable telomere shortening. A. TRF blots of untreated (left), TDF-treated (right) HT29 cells. PDL at which TRF was analyzed is shown above each lane. ...
Telomeres are ribonucleoprotein structures at the end of chromosomes composed of telomeric DNA, specific-binding proteins and noncoding RNA (TERRA). Despite their importance in preventing chromosome instability, little is known about the crosstalk between these three elements during the formation of the germ line. Here, we provide evidence that both TERRA and the telomerase enzymatic subunit (TERT) are components of telomeres in mammalian germ cells. We found that TERRA co-localizes with telomeres during mammalian meiosis and that its expression progressively increases during spermatogenesis, until the beginning of spermiogenesis. While both TERRA levels and distribution would be regulated in a gender-specific manner, telomere-TERT co-localization appears to be regulated based on species-specific characteristics of the telomeric structure. Moreover, we found that TERT localization at telomeres is maintained all through spermatogenesis as a structural component without affecting telomere ...
Single-stranded DNA-dependent ATP-dependent helicase. Involved in non-homologous end joining (NHEJ) DNA double strand break repair. DNA-binding is sequence-independent but has a high affinity to nicks in double-stranded DNA and to the ends of duplex DNA. Binds to naturally occurring chromosomal ends, and therefore provides chromosomal end protection. Appears to have a role in recruitment of telomerase and CDC13 to the telomere and the subsequent telomere elongation. Required also for telomere recombination to repair telomeric ends in the absence of telomerase. KU70, of the KU70/KU80 heterodimer, binds to the stem loop of TLC1, the RNA component of telomerase. Involved in telomere maintenance. Interacts with telomeric repeats and subtelomeric sequences thereby controlling telomere length and protecting against subtelomeric rearrangement. Maintains telomeric chromatin, which is involved in silencing the expression of genes located at the telomere. Required for mating-type switching.
One of the factors limiting indefinite proliferation of somatic cells is telomere length [1], [2]. Indeed, the inability to fully replicate both strands of a linear DNA molecule is expected to lead to gradual shortening of telomeres in cells that do not express telomerase. Telomere shortening may be even more severe, if the replication machinery fails to reach the telomeric end. Indeed, the highly repetitive primary structure of telomeres [3], the presence of G‐quadruplexes [4], DNA-RNA hybrids [5], [6], and T‐loops [7], as well as the extensive telomeric heterochromatinization [8], challenge the process of terminal DNA replication and make telomeres prone to fork collapse, similar to common fragile sites [9], [10]. Fork collapse within a telomere is unlikely to be resolved by incoming forks or dormant forks, since human telomeres are thought to be devoid of replication origins. Instead, telomere replication is normally dependent on a single origin, located at the subtelomeric regions [11]. ...
One of the factors limiting indefinite proliferation of somatic cells is telomere length [1], [2]. Indeed, the inability to fully replicate both strands of a linear DNA molecule is expected to lead to gradual shortening of telomeres in cells that do not express telomerase. Telomere shortening may be even more severe, if the replication machinery fails to reach the telomeric end. Indeed, the highly repetitive primary structure of telomeres [3], the presence of G‐quadruplexes [4], DNA-RNA hybrids [5], [6], and T‐loops [7], as well as the extensive telomeric heterochromatinization [8], challenge the process of terminal DNA replication and make telomeres prone to fork collapse, similar to common fragile sites [9], [10]. Fork collapse within a telomere is unlikely to be resolved by incoming forks or dormant forks, since human telomeres are thought to be devoid of replication origins. Instead, telomere replication is normally dependent on a single origin, located at the subtelomeric regions [11]. ...
Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related
Understanding the molecular processes that drive cellular replicative senescence is critical to understanding human longevity. Much attention has focused on telomere length as a determinant of replicative capacity (1). Telomeres are nucleoprotein structures composed of species-specific tandemly repeated, G-rich DNA sequences that cap and protect chromosome ends from nucleolytic attack and degradation (2). Telomeres also conceal linear chromosome ends from inappropriate attempts at double-strand break (DSB) repair that might otherwise join chromosomes end-to-end. The preservation of natural chromosome ends and the rejoining of broken DNA ends, both of which are essential for preserving genomic integrity, rely on a common subset of proteins (3), and both decline with advancing age (4, 5).. The G-rich nature of telomeric DNA renders it susceptible to G-quadruplex formation, oxidative damage, and alkylation by electrophiles (6). Telomeres are also unique in their chromatin composition, being bound ...
The Patient Telomere Score is calculated based on the patients average telomere length in peripheral whole blood cells. This average is then compared to telomere lengths from a population sample in the same age range as the patient to determine the patients percentile score. What do the results mean to the patient and the doctor? Cellular attrition by analyzing the rate at which changes in average Telomere length occur over time. Cells are being lost and replaced. (Cellular attrition) What are the nutritional implications on telomere length and repair? An inflammatory diet, or one that increases oxidative stress, will shorten telomeres faster. This includes refined carbohydrates, fast foods, processed foods, sodas, artificial sweeteners, trans fats and saturated fats. A diet with a large amount and variety of antioxidants that improves oxidative defense and reduces oxidative stress will slow telomere shortening. Consumption of 10 servings of fresh and relatively uncooked fruits and vegetables, ...
Why is this important" In embryonic cells (and some stem cells), an enzyme called telomerase rebuilds the telomere so that the cells can keep dividing. Over time, this telomerase dwindles and eventually the telomere shortens and the cell becomes inactive. In cancer cells, the telomerase enzyme keeps rebuilding telomeres long past the cells normal lifetime. The cells become "immortal", endlessly dividing, resulting in a tumor. Researchers estimate that telomere maintenance activity occurs in about 90% of human cancers. But the mechanism by which this maintenance takes place is not well understood. The researchers discovered that the RNA in the telomere is regulated by a protein in the telomerase enzyme. Their discovery may thus uncover key elements of telomere function ...
TY - JOUR. T1 - Telomere length in peripheral blood leukocytes and risk of renal cell carcinoma. AU - Park, Jong Y.. AU - Luu, Hung N.. AU - Park, Hyun Y.. AU - Lin, Hui Yi. AU - Radlein, Selina. AU - Di Pietro, Giuliano. AU - Yeo, Chang Dong. AU - Kim, Seung Joon. AU - Kang, Nahyeon. AU - Antwi, Samuel. AU - Sexton, Wade J.. AU - Spiess, Philippe E.. AU - Dickinson, Shohreh. AU - Parker, Alexander. PY - 2019/1/1. Y1 - 2019/1/1. N2 - Background: Telomeres are essential for chromosomal stability and may play a key role in carcinogenesis. Telomere length is suggested as a tentative biomarker of risk for renal cell carcinoma (RCC). However, results of previous association studies between telomere length and risk for RCC are inconsistent. Methods: We evaluated RCC risk in relation to peripheral blood leukocyte telomere length using a hospital-based case-control study of 169 RCC cases and 189 controls. Cases were histologically-confirmed RCC patients who were treated at the Moffitt Cancer Center ...
An SGA approach to discover cdc13-1ts supressors. Telomeres, the DNA-protein complexes at the end of eukaryotic chromosomes, are essential for chromosomal stability. In yeast, the telomeric single-strand binding protein Cdc13p has multiple important roles related to telomere maintenance: (1) telomeric"capping"--protection of telomeres by forming complexes with yKu70/80 and with Stn1p/Ten1p; (2) positive regulation of telomere replication via interaction with Est1p, which is a part of telomerase; (3) negative regulation of telomerase by the recruitment of telomere elongation suppressors Stn1p and Ten1p. In an attempt to identify genes that are involved in the deleterious outcome of an absence of Cdc13p, we screened the yeast gene knock-out library for genes that could suppress the growth defect of cdc13-1 cells at 33ê C. For this purpose, we performed an SGA array experiment. We scored for the ability of double mutant haploids to grow at 33ê C. Eventually, we hoped to find the elusive genes ...
Laure Crabbe, Ramiro E. Verdun, Candy I. Haggblom, and Jan Karlseder http://sageke.sciencemag.org/cgi/content/abstract/2004/50/or22 Abstract: Science 306, 1951-1953 (2004).. Cells from Werner syndrome patients are characterized by slow growth rates, premature senescence, accelerated telomere shortening rates, and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here we report that cells lacking WRN exhibit deletion of telomeres from single sister chromatids. Only telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. We propose that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability.. [Abstract/Full Text]. ...
We have isolated STN1, an essential Saccharomyces cerevisiae gene, as a suppressor of the cdc13-1 mutation. A synthetic lethal interaction between a temperature-sensitive mutant allele of STN1, stn1-13, and cdc13-1 was observed. Stn1 and Cdc13 proteins displayed a physical interaction by two-hybrid analysis. As shown previously for cdc13-1, stn1-13 cells at the restrictive temperature accumulate single-stranded DNA in subtelomeric regions of the chromosomes, but to a lesser extent than cdc13-1 cells. In addition, both Cdc13 and Stn1 were found to be involved in the regulation of telomere length, mutations in STN1 or CDC13 conferring an increase in telomere size. Loss of Stn1 function activated the RAD9 and MEC3 G2/M checkpoints, therefore confirming that DNA damage is generated. We propose that Stn1 functions in telomere metabolism during late S phase in cooperation with Cdc13 ...
Telomeres, which are found at the end of eukaryotic linear chromosomes, are essential for chromosome maintenance and genomic stability (1). Mammalian telomeres are composed of repetitive d-(TTAGGG) sequences and telomere-specific "shelterin" complex proteins, which protect the chromosome ends from being recognized as DNA damage and preventing end-to-end chromosomal fusions (2). The shelterin proteins (TRF1, TRF2, POT1, TIN2, TPP1, and RAP1) form a protective complex that is present at telomeres throughout the cell cycle (3). Because of the "end-replication problem," oxidative damage and other replication-associated end-processing events, telomeres progressively shorten with each round of DNA replication in normal somatic cells (4). The ribonucleoprotein enzyme complex telomerase counteracts telomere shortening by adding hexameric telomeric DNA (TTAGGG) repeats to the end of linear chromosomes in cancer cells but only partially counteracts progressive telomere shortening in some normal human ...
Figure 3. Mutations in STN1 result in abnormal telomere phenotypes. (A) DNA samples, prepared from PBLs of patient P1, her heterozygous father (F1), and a noncarrier sibling (S1) and patient P2, his heterozygous mother (M2), and two independent control samples (C), were analyzed by in-gel hybridization. Duplicated lanes were electrophoresed in the same gel, and then separated and hybridized to a G-rich or C-rich telomeric probe, as indicated above the panels. After native hybridization to detect single-stranded telomeric DNA (top), the gels were denatured and rehybridized with the same probes to detect the overall duplex telomeric DNA (bottom). Treatment with exonuclease I is indicated above the lanes. (B) Graphic illustration of the mean telomere length for the patients and their family members, calculated based on the following number of independent measurements of four in-gels and two Southern analyses: P1:6, M1:3, F1:3, S1:3, P2:9, M2:3, F2:1, C1:2, and C2:3. (C) Graphic illustration of the ...
Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age‑related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, ...
POT1 is one of the six core components of the human telomeric protein complex (reviewed in de Lange, 2005). This complex is composed of TRF1, TRF2, TIN2, TPP1 (previously known as PIP1, PTOP, or TINT1), Rap1, and POT1, which are thought to fulfill the two main functions of telomeres: the recruitment and regulation of telomerase, and the protection of chromosome ends. Defects in telomere protection activate the DNA damage response, leading to a DNA damage signal and inappropriate DNA repair reactions at chromosome ends. The cell cycle arrest resulting from telomere dysfunction is thought to be responsible for the finite lifespan of human cells lacking telomerase.. The current challenge is to understand how the telomeric complex protects chromosome ends from being recognized as sites of DNA damage. One approach is to define which repair and signaling pathways are repressed at natural chromosome ends by studying the events at dysfunctional telomeres. This approach has shown that chromosome ends are ...
Acts both as a regulator of telomere function and as a transcription regulator. Involved in the regulation of telomere length and protection as a component of the shelterin complex (telosome). In contrast to other components of the shelterin complex, it is dispensible for telomere capping and does not participate in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair. Instead, it is required to negatively regulate telomere recombination and is essential for repressing homology-directed repair (HDR), which can affect telomere length. Does not bind DNA directly: recruited to telomeric double-stranded 5-TTAGGG-3 repeats via its interaction with TERF2. Independently of its function in telomeres, also acts as a transcription regulator: recruited to extratelomeric 5-TTAGGG-3 sites via its association with TERF2 or other factors, and regulates gene expression. When cytoplasmic, associates with the I-kappa-B-kinase (IKK) complex and acts as a regulator of the NF-kappa-B
Depletion of hematopoietic stem cell reserves, expressed as the shortening of leukocyte telomere length (LTL), sets a limit on longevity and increases the risk...
TELOMERES are nucleoprotein complexes at the termini of linear eukaryotic chromosomes that perform a critical role in maintaining genome stability. At the DNA level, telomeres typically comprise long double-stranded tracts of a repetitive GT/CA-rich sequence, terminating in a short single-stranded 3′ overhang that corresponds to the strand bearing the G-rich repeats. A large number of proteins associate with the telomere repeats to form a structure that allows telomeres to act as "caps" that protect chromosome ends from degradation and illegitimate end-to-end fusions. Chromosomes are considered capped if they preserve the physical integrity of the telomere while allowing cell division to proceed (Blackburn 2000). Proteins that bind to the duplex portion of telomeres, such as TRF1 and TRF2 in mammalian cells and Rap1p in Saccharomyces cerevisiae, as well as proteins that bind the single-strand overhang, such as POT1 in mammalian cells and Cdc13p in S. cerevisiae, are essential for proper ...
Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating lymphocytes. The present study investigated whether this effect was further amplified in smokers who develop chronic obstructive pulmonary disease.. Telomere length was determined by fluorescence in situ hybridisation in circulating lymphocytes harvested from 26 never-smokers, 24 smokers with normal lung function and 26 smokers with moderate-to-severe airflow obstruction (forced expiratory flow in one second 48±4% predicted).. In contrast to never-smokers, telomere length significantly decreased with age in smokers. There was also a dose-effect relationship between the cumulative long-life exposure to tobacco smoking (pack-yrs) and telomere length. The presence and/or severity of chronic airflow obstruction did not modify this relationship.. The results of ...
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which
So, poorly functioning mitochondria lead to telomere shortening, and telomerase somehow improves mitochondrial function to prevent that shortening. This is in place of the more expected path of undoing ongoing telomere shortening by adding extra repeat sequences to the end of the telomeres - that being the better understood function of telomerase.. Damaged mitochondria are a fundamental root cause of age-related degeneration far above and beyond the matter of telomeres. If telomerase acts to improve the state of mitochondria, this might explain why telomere length correlates so well with general measures of health in the old. It might even be the case that, setting aside cancer for one moment, telomere length really isnt that important in comparison to your mitochondrial health.. This all cries out for more research - the prospect of reducing two thorny problems down to one in the development of medical technologies to repair and prevent aging is very welcome. Regardless of the outcome, efforts ...
Objective: Telomere length is associated with poorer lung health in older adults, possibly from cumulative risk factor exposure, but data are lacking in pediatric and population-based cohorts. We examined associations of telomere length with lung function in children and mid-life adults.Methods: Data were drawn from a population-based cross-sectional study of 11 to 12 year-olds and mid-life adults. Lung function was assessed by spirometric FEV1, FVC, FEV1 /FVC ratio, and MMEF25-75. Telomere length was measured by quantitative polymerase chain reaction from blood and expressed as the amount of telomeric genomic DNA to the beta-globin gene (T/S ratio). Associations of telomere length with spirometric parameters were tested by linear and logistic regression models, adjusting for potential confounders of sex, age, body mass index, socioeconomic position, physical activity, inflammation, asthma, pubertal status, and smoking.Results: Mean T/S ratio was 1.09 (n = 1206; SD 0.55) in children and 0.81 (n ...
POSTDOCTORAL POSITIONS AVAILABLE TO STUDY TELOMERE SIZE REGULATION AND TELOMERIC SILENCING IN SACCHAROMYCES CEREVISIAE. I am seeking additional qualified postdoctoral researchers to study one of two ongoing projects: a) the role of the telomere-binding protein RAP1 in telomere size control and telomeric silencing (see Lustig et al. MCB 16: 2483-2495, 1996); and b) the characterization of a novel process, called telomeric rapid deletion (Li and Lustig, Genes Dev. 10:1310-1326, 1996), that appears to combine elements of intrachromatid recombination and pairing of non-homologous telomeres to regulate telomere size. Applicants should have a background in molecular biology and/or genetics. Interested applicants background can respond by e-mail or at the address listed below. Arthur J. Lustig Associate Professor Department of Biochemistry SL43 Tulane University Medical Center 1430 Tulane Avenue New Orleans, LA 70112 504-584-3688 504-584-2739(fax ...
Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a ...
Mammalian telomeres are inherently heterochromatic. While enhanced telomere maintenance is evident in malignant cancers, some cancers appear to maintain telomeres by neither the common telomerase nor the alternative telomere repeat recombination mechanisms. Specifically, the roles of epigenetic modifications in telomere protection are largely unknown in human cancers. I have combined newly developed cellular and molecular approaches to show that in some cancer cell types, experimentally enhanced heterochromatinization localized specifically at telomeres reduced damage-induced foci at telomeres, suggesting augmentation of telomere stability. These results lead to the intriguing hypothesis that manipulating the epigenetic status at telomeres may be exploited to elicit damage at the telomeres of cancer cells as a novel approach to fight cancer. My current work in progress focuses on identifying novel chromatin modifiers that weaken telomere protection by modulating telomere compaction. It is ...
1. VerdunRE, KarlsederJ (2007) Replication and protection of telomeres. Nature 447: 924-931.. 2. GilsonE, GeliV (2007) How telomeres are replicated. Nat Rev Mol Cell Biol 8: 825-838.. 3. BlackburnEH, GreiderCW, SzostakJW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12: 1133-1138.. 4. PalmW, de LangeT (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42: 301-334.. 5. ArmaniosM, BlackburnEH (2012) The telomere syndromes. Nat Rev Genet 13: 693-704.. 6. MiyoshiT, KanohJ, SaitoM, IshikawaF (2008) Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science 320: 1341-1344.. 7. MoserBA, NakamuraTM (2009) Protection and replication of telomeres in fission yeast. Biochem Cell Biol 87: 747-758.. 8. KanohJ, IshikawaF (2001) spRap1 and spRif1, recruited to telomeres by Taz1, are essential for telomere function in fission yeast. Curr Biol 11: 1624-1630.. 9. TomitaK, CooperJP (2008) Fission yeast Ccq1 is ...
Oocytes may undergo two types of aging. The first is induced by exposure to an aged ovarian microenvironment before being ovulated, known as reproductive or maternal aging, and the second by either a prolonged stay in the oviduct before fertilization or in vitro aging prior to insemination, known as postovulatory aging. However, the molecular mechanisms underlying these aging processes remain to be elucidated. As telomere shortening in cultured somatic cells triggers replicative senescence, telomere shortening in oocytes during reproductive and postovulatory aging may predict developmental competence. This study aimed to ascertain the mechanisms underlying altered telomere biology in mouse oocytes during reproductive and postovulatory aging. We studied Tert expression patterns, telomerase activity, cytosolic reactive oxygen species (ROS) production, and telomere length in fresh oocytes from young versus reproductively-aged female mice retrieved from oviducts at 14 h post-human chorionic gonadotropin
1. OlovnikovAM. 1973 A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41 181 190. 2. LongheseMP. 2008 DNA damage response at functional and dysfunctional telomeres. Genes Dev 22 125 140. 3. GreiderCW. BlackburnEH. 1985 Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43 405 413. 4. LydallD. 2009 Taming the tiger by the tail: modulation of DNA damage responses by telomeres. EMBO J 28 2174 2187. 5. FisherTS. ZakianVA. 2005 Ku: a multifunctional protein involved in telomere maintenance. DNA Repair (Amst) 4 1215 1226. 6. BoultonSJ. JacksonSP. 1998 Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J 17 1819 1828. 7. MaringeleL. LydallD. 2002 EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint ...
Telomeres, the complex of repetitive DNA and associated proteins at chromosome ends, are essential for chromosome stability. They prevent chromosome ends from fusing and from being recognized as damaged DNA. The telomeres from several organisms have been shown to be located at the nuclear periphery. Transcriptional repression and heterochromatin formation are other processes intimately associated with telomeres and assigned to functional subdomains within the nucleus (reviewed in Greider, 1996; Cockell and Gasser, 1999). Telomeric DNA generally consists of tandemly repeated, short G‐rich sequences and ends with a 3′ overhang, formed by the degradation of the ultimate primer used for synthesizing the lagging strand during DNA replication (reviewed in de Lange, 1995). It was recently observed that telomeres in mammalian cells, ciliates and trypanosomes end with large T loops (for telomere loops), presumably formed by invasion of the 3′ telomeric overhang into the duplex telomeric repeat ...