Telomeres, telomerase and senescence

Eukaryotic chromosomes end with tandem repeats of simple sequences. These GC rich repeats allow telomere replication and stabilize chromosome ends. Telomere replication involves an equilibrium of sequence loss and addition at the ends of chromosomes. Repeats are added de novo by telomerase, an unusual DNA polymerase. Telomerase is an RNP in which an essential RNA component provides the template for the added telomere repeats. Telomere length maintenance plays an essential role in cell viability.     

Telomeres, telomerase and malignant transformation

Human cancer arises in a stepwise process by the accumulation of genetic alterations in oncogenes, tumor suppressor genes and other genes involved in the regulation of cell growth and proliferation. Many genes, important for the pathogenesis of various cancers and the pathways through which they act, have been characterized over the past decades. Nevertheless, recent successes in experimental models of immortalization and malignant transformation of human cells indicate that the disruption of a limited number of cellular pathways is sufficient to induce a cancerous phenotype in a wide variety of normal cells. In this context, immortalization is an essential prerequisite for the formation of a tumor cell. Besides classical cancer related pathways as the pRB and p53 tumor suppressor pathway or the ras signaling pathway, the maintenance of telomeres plays an essential role in both of these processes. Alterations in telomere biology both suppress and facilitate malignant transformation by regulating genomic stability and cellular life span. This review will summarize recent advances in the understanding of the molecular mechanisms of malignant transformation in human cells and the role of telomere maintenance in these processes. This ultimately leads to the development of cellular models of human cancer that phenocopy the corresponding disease. Furthermore, in the future these models could provide an ideal basis for the testing of novel chemopreventive or therapeutic approaches in the treatment of different types of human cancer.     

端粒、端粒酶与细胞衰老

端粒和端粒酶是现代生物学研究的热点,端粒的缺失与细胞的衰老,端粒酶的活性与细胞的老化及癌化均有密切的关系。章综述了端粒和端粒酶的结构和功能,及其与细胞衰老的关系,并在此基础之上展望了端粒酶在抗衰老、抑制肿瘤等方面的应用。     

Telomeres and telomerase activity in pig tissues

The current state of the art concerning telomeres and telomerase stems almost exclusively from the analysis of protozoa, yeast, and a small number of mammals. In the present study, we confirm that the pig telomeric sequence is indeed T(2)AG(3), as previously suggested. By making use of sequence analysis of pig telomeric DNA variant telomeric repeats in the medial region of the telomeres, interspersed with canonical T(2)AG(3) repeats, were identified. This telomere organization is similar to the one present in humans. Analysis of terminal restriction fragments showed that the majority of telomeres from different pig tissues are longer than in humans but shorter than in Mus musculus. Telomeres from spermatozoa were found to be longer, ranging in size between 13 and 44 kb. Most of the somatic pig tissues expressed significant levels of telomerase activity, a situation more similar to mouse and that contrasts with the one in humans and dog. Moreover, the analysis of sperm cells from different epididymal compartments of an adult animal showed that telomerase activity is absent in maturing spermatozoa, suggesting that sperm telomere elongation is restricted during spermatogenesis.     

Telomeres and telomerase in normal and cancer stem cells

Differences between normal adult tissue stem cells and cancer stem/initiating cells remain poorly defined. For example, it is controversial if cancer stem cells can become fully quiescent, require a stem cell niche, are better at repairing DNA damage than the bulk of the cancer cells, and if and how they regulate symmetric versus asymmetric cell divisions. This minireview will not only provide our personal views to address some of these outstanding questions, but also present evidence that an understanding of telomere dynamics and telomerase activity in normal and cancer stem cells may provide additional insights into how tumors are initiated, and how they should be monitored and treated.     

Telomeres and telomerase in aging,regeneration and cancer

The finding that telomere shortening limits the replicative lifespan of primary human cells has fueled speculations that telomere shortening plays a role during aging and regeneration of tissues in vivo. Support for this hypothesis comes from studies showing telomere shortening in a variety of human tissues as a consequence of aging and chronic disease. Studies in telomerase-deficient mice have given first experimental support that telomere shortening limits the replicative potential of organs and tissues in vivo and have identified telomerase as a promising target to treat regenerative disorders induced by telomere shortening. A potential downside of such an approach could be the development of malignant tumors, which has been linked to reactivation of telomerase in human cancers. In telomerase-deficient mice, telomere shortening showed a dual role in tumorigenesis, enhancing the initiation of tumors by induction of chromosomal instability but inhibiting tumor progression by induction of DNA-damage responses. The success in using telomerase activation for the treatment of regenerative disorders could depend on which of the mechanisms of telomere shortening is dominantly effecting carcinogenesis.     

Telomeres,telomerase, and stability of the plant genome

Telomeres, the complex nucleoprotein structures at the ends of linear eukaryotic chromosomes, along with telomerase, the enzyme that synthesizes telomeric DNA, are required to maintain a stable genome. Together, the enzyme and substrate perform this essential service by protecting chromosomes from exonucleolytic degradation and end-to-end fusions and by compensating for the inability of conventional DNA replication machinery to completely duplicate the ends of linear chromosomes. Telomeres are also important for chromosome organization within the nucleus, especially during mitosis and meiosis. The contributions of telomeres and telomerases to plant genome stability have been confirmed by analysis of Arabidopsis mutants that lack telomerase activity. These mutants have unstable genomes, but manage to survive up to ten generations with increasingly shortened telomeres and cytogenetic abnormalities. Comparisons between telomerase-deficient Arabidopsis and telomerase-deficient mice reveal distinct differences in the consequences of massive genome damage, probably reflecting the greater developmental and genomic plasticity of plants.     

Telomeres and telomerase: broad effects on cell growth.

During the past year, major advances have been made in understanding the link between telomerase expression and cell immortality. Studies of yeast telomeres have revealed an unexpected role for the non-homologous end-joining machinery in telomere maintenance and have provided the first definitive evidence that telomeres play a critical role in meiosis. Identification of new telomere proteins has led to a better understanding of vertebrate telomere structure and function.     

Telomeres and telomerase: more than the end of the line

Early studies of telomerase suggested that telomeres are maintained by an elegant but relatively simple and highly conserved mechanism of telomerase-mediated replication. As we learn more, it has become clear that the mechanism is elegant but not as simple as first thought. It is also evident that, although many species use similar, sometimes identical, DNA sequences for telomeres, these species express their own individuality in the way they regulate these sequences and, perhaps, in the additional tasks that they have imposed on their telomeric DNA. The striking similarities between telomeres in different species have revealed much about chromosome ends; the differences are proving to be equally informative. In addition to the differences between species that use telomerase, there are also a few exceptional organisms with atypical telomeres for which no telomerase activity has been detected. This review addresses recent studies, the insights they offer, and, perhaps more importantly, the questions they raise. Received: 14 January 1999 / Accepted: 15 January 1999     

Telomeres and telomerase dance to the rhythm of the cell cycle

The stability of the ends of linear eukaryotic chromosomes is ensured by functional telomeres, which are composed of short, species-specific direct repeat sequences. The maintenance of telomeres depends on a specialized ribonucleoprotein (RNP) called telomerase. Both telomeres and telomerase are dynamic entities with different physical behaviors and, given their substrate-enzyme relation, they must establish a productive interaction. Regulatory mechanisms controlling this interaction are key missing elements in our understanding of telomere functions. Here, we review the dynamic properties of telomeres and the maturing telomerase RNPs, and summarize how tracking the timing of their dance during the cell cycle will yield insights into chromosome stability mechanisms. Cancer cells often display loss of genome integrity; therefore, these issues are of particular interest for our understanding of cancer initiation or progression.     

Telomeres in drag: Dressing as DNA damage to engage telomerase

The telomere field concentrates both on mechanisms of telomere synthesis and the mechanisms by which telomeres protect chromosome termini from fusion and degradation. Recent studies show that the DNA damage response (DDR) machinery, formerly thought to be the culprit in deleterious telomeric fusion and degradation reactions, plays an active role not only in telomere protection but also in regulating telomere synthesis. Conversely, semi-conservative DNA replication, responsible for the bulk of telomere synthesis, now appears to be a pivotal event on the road to telomere de-protection. These advances prompt the notion that the two guises of telomere function are intricately entangled. Indeed, telomeres appear to expose themselves to the DDR upon passage of the replication fork, in turn attracting telomerase.     

Telomeres and telomerase in the fetal origins of cardiovascular disease: a review

Telomeres are noncoding functional DNA repeat sequences at the ends of chromosomes that decrease in length by a predictable amount at each cell division. When the telomeres become critically short, the cell is no longer able to replicate and enters cellular senescence. Recent work has shown that within individuals, telomere length tracks with cardiovascular health and aging and is also affected by growth variation, both prenatally and postnatally. Therefore telomere length can be a marker of both growth history (cell division) and tissue function (senescence). Relationships between early growth and later health have emerged as a research focus in the epidemiology of chronic diseases of aging, such as heart disease and diabetes. The "fetal origins" literature has demonstrated that hormonal and nutritional aspects of the intrauterine environment not only affect fetal growth but also can permanently alter the metabolic program of the individual. Smaller infants tend to have a higher risk of developing cardiovascular disease. Much less attention has been paid to possible genetic links between the processes of early growth and later disease. Our aim in this review is to summarize evidence for one such genetic mechanism, telomere attrition, that may underlie the fetal origins of cardiovascular disease and to discuss this mechanism in light of the evolution of senescence.     

Telomeres and telomerase: their mechanisms of action and the effects of altering their functions

The molecular features of telomeres and telomerase are conserved among most eukaryotes. How telomerase and telomeres function and how they interact to promote the chromosome-stabilizing properties of telomeres are discussed here.