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 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.     

Estrone sulfatase activity in guinea pig tissues

Estrone sulfatase activity is widespread in guinea pig tissues. Whole homogenates of adult testis. uterus. lung, adrenal, amnion, ovary, chorion, small intestine, placenta, spleen, kidney and liver exhibit approximately descending order of specific activity. Certain properties, including pH requirement, lack of inhibition by inorganic sulfate and magnitude of estimated K_mvalues, are similar to that for arylsulfatase C of rat liver. Of the subcellular fractions prepared from guinea pig tissues, microsomes exhibit the highest specific activity although considerable enzyme activity remains associated with large cellular fragments sedimenting at 750 g. The sulfatase activity is readily inhibited by inorganic phosphate even when substrate concentration satisfies zero order kinetics. Rat liver arylsulfatase C is not inhibited under these conditions. Sensitivity of the guinea pig enzyme activity to inhibition by a variety of steroids and related compounds, is markedly less than for rat liver. Diethylstilbestrol (DES) strongly inhibits the rat liver enzyme but has little effect on the guinea pig liver system. Guinea pig testicular activity is suppressed to a degree intermediate between these extremes by increasing DES concentration. In guinea pig lung. kidney, and possibly liver, elevated fetal enzyme activities decrease from neonatal to adult life. Teslicular activity appears to follow the opposite trend. Uterine enzyme activity is not markedly affected by pregnancy.     

肾癌组织中端粒酶活性的测定与分析

端粒酶 (Ｔｅｌｏｍｅｒａｓｅ)是一种核糖核蛋白 ,依赖酶分子中的ＲＮＡ模板 ,通过逆转录合成染色体末端的端粒。近年来研究证实 ,端粒酶与细胞衰老及细胞分裂过程密切相关 ,尤其在恶性肿瘤组织中活性异常高。因此通过测定肿瘤组织、癌旁细胞及脱落细胞等端粒酶活性 ,可用于癌症的临床诊断、疗效观察、愈后及病理机制的研究。国外已经有对肾癌组织的端粒酶活性进行测定但都为定性 ,国内未见报道。本实验采用ＴＲＡＰ -ＥＬＩＳＡ技术对肾癌组织中端粒酶活性进行定量检测 ,现将结果报告如下。1　材料与方法1 1　样本来源 :组织标本均来自白…     

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 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: 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     

3-Mercaptopyruvate sulfurtransferase activity in guinea pig and rat tissues

Activities of 3-mercaptopyruvate sulfurtransferase (EC 2.8.1.2) in guinea pig tissues were determined and compared with those in the corresponding rat tissues. The activities in guinea pig tissues were found to be very low. The activity in the liver was 145.9 mumol pyruvate formed per g of fresh tissue per 15 min. This was 1/50 of the activity in the rat liver. Activities in the kidney and brain were 1/100 of the corresponding rat tissues. Those in the erythrocyte and heart were negligibly low and far less than 1/1000 of these tissues in the rat. Similarities between the guinea pig and patients with beta-mercaptolactate-cysteine disulfiduria are discussed.     

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.