Telomeres: Cancer to Human Aging

Departments of Cell Biology and Physiology and of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Annual Review of Cell and Developmental Biology (Impact Factor: 16.66). 02/2006; 22(1):531-57. DOI: 10.1146/annurev.cellbio.22.010305.104518
Source: PubMed


The cell phenotypes of senescence and crisis operate to circumscribe the proliferative potential of mammalian cells, suggesting that both are capable of operating in vivo to suppress the formation of tumors. The key regulators of these phenotypes are the telomeres, which are located at the ends of chromosomes and operate to protect the chromosomes from end-to-end fusions. Telomere erosion below a certain length can trigger crisis. The relationship between senescence and telomere function is more complex, however: Cell-physiological stresses as well as dysfunction of the complex molecular structures at the ends of telomeric DNA can trigger senescence. Cells can escape senescence by inactivating the Rb and p53 tumor suppressor proteins and can surmount crisis by activating a telomere maintenance mechanism. The resulting cell immortalization is an essential component of the tumorigenic phenotype of human cancer cells. Here we discuss how telomeres are monitored and maintained and how loss of a functional telomere influences biological functions as diverse as aging and carcinogenesis.

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    • "Escape from senescence results in critically short telomeres and apoptosis [5]. However, on occasion, cells evade apoptosis by reactivating telomerase, which results in renewed telomere length maintenance and cellular immortalization, a hallmark of 80–95% of cancers [5] [6]. In contrast, telomerase or telomere maintenance deficiencies in proliferative cell populations cause organ failure in a class of telomere-shortening diseases, examples of which include dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anemia [7] [8]. "
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    ABSTRACT: Telomere maintenance is a highly coordinated process, and its misregulation is linked to cancer as well as telomere-shortening syndromes. Recent studies have shown that the TEL-patch - a cluster of amino acids on the surface of the shelterin component TPP1 - is necessary for the recruitment of telomerase to the telomere in human cells. However, there has been only basic biochemical analysis of the role of TPP1 in the telomerase recruitment process. Here we develop an in vitro assay to quantitatively measure the contribution of the TEL-patch to telomerase recruitment - binding and extension of the first telomeric repeat. We also demonstrate that the TEL-patch contributes to the translocation step of the telomerase reaction. Finally, our quantitative observations indicate that the TEL-patch stabilizes the association between telomerase and telomeric DNA substrates, providing a molecular explanation for its contributions to telomerase recruitment and action. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular Biology 01/2015; 427(6). DOI:10.1016/j.jmb.2015.01.008 · 4.33 Impact Factor
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    • "The transcriptional factor p53 is a tumor suppressor protein that is activated by various stresses, such as oncogenic stimuli, hypoxia , and oxidative stress (Serrano and Blasco, 2001; Stewart and Weinberg, 2006). It is thought to be a defensive mechanism against malignant transformation. "
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    ABSTRACT: Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.
    Cell Reports 05/2014; 7(5). DOI:10.1016/j.celrep.2014.04.046 · 8.36 Impact Factor
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    • "Controversy persists over the association of p53 mutations with tumor telomere length and cancer cell immortalization via telomere maintenance repair pathways. Both telomerase activation and ALT have been reported to function independently of p53 mutation [23], but some studies have determined that telomere dysfunction with associated telomerase activation may be more likely to intensify tumor promotion in the face of p53 mutation [29]. "
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    ABSTRACT: Colorectal cancer (CRC) tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN) and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS) and is historically considered to be chromosomally unstable (CIN+). However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-). MSS CIN- tumors have not been assessed for telomere attrition. MSS rectal cancers from patients ≤50 years old with Stage II (B2 or higher) or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]). Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH. Tumors were classified as chromosomally stable (CIN-) and chromosomally instable (CIN+) by degree of DNA copy number changes. CIN- tumors (35%; n=6) had fewer copy number changes (<17% of their clones with DNA copy number changes) than CIN+ tumors (65%; n=13) which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066) and in those in which telomerase was not activated (p=0.004). Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040); and tended to be CIN+ (p=0.0949). MSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.
    PLoS ONE 11/2013; 8(11):e80015. DOI:10.1371/journal.pone.0080015 · 3.23 Impact Factor
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