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Telomere length and telomere shortening are thought to be critical cellular attributes and processes that are related to an individual's life span and fitness. The general pattern across most taxa is that after birth telomere length gradually decreases with age. Telomere protection and restoration mechanisms are usually assumed to reduce the rate of shortening or at most keep telomere length constant. However, here we have compiled a list of 26 articles showing that there is an increasing number of studies reporting apparent elongation of telomeres (i.e., a net increase in TL from timet to timet+1) often in a considerable proportion of the individuals studied. Moreover, the few studies which have studied telomere elongation in detail show that increases in telomere length are unlikely to be due to measurement error alone. In this article, we argue that episodes of telomere elongation deserve more attention as they could reflect individual strategies to optimise life histories and maximise fitness, which may not be reflected in the overall telomere dynamics patterns. We propose that patterns of telomere (net) elongation may be partly determined by other factors than those causing telomere shortening, and therefore deserve analyses specifically targeted to investigate the occurrence of telomere elongation. We elaborate on two ecological hypotheses that have been proposed to explain patterns of telomere elongation (the 'excess resources elongation' and the 'last resort elongation' hypothesis) and we discuss the current evidence for (or against) these hypotheses and propose ways to test them.

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Somatic human cells can divide a finite number of times, a phenomenon known as the Hayflick limit. It is based on the progressive erosion of the telomeric ends each time the cell completes a replicative cycle. Given this problem, researchers need cell lines that do not enter the senescence phase after a certain number of divisions. In this way, more lasting studies can be carried out over time and avoid the tedious work involved in performing cell passes to fresh media. However, some cells have a high replicative potential, such as embryonic stem cells and cancer cells. To accomplish this, these cells express the enzyme telomerase or activate the mechanisms of alternative telomere elongation, which favors the maintenance of the length of their stable telomeres. Researchers have been able to develop cell immortalization technology by studying the cellular and molecular bases of both mechanisms and the genes involved in the control of the cell cycle. Through it, cells with infinite replicative capacity are obtained. To obtain them, viral oncogenes/oncoproteins, myc genes, ectopic expression of telomerase, and the manipulation of genes that regulate the cell cycle, such as p53 and Rb, have been used.

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ZSCAN4 is a transcription factor that plays a pivotal role during early embryonic development. It is a unique gene expressed specifically during the first tide of de novo transcription during the zygotic genome activation. Moreover, it is reported to regulate telomere length in embryonic stem cells and induced pluripotent stem cells. Interestingly, ZSCAN4 is expressed in approximately 5% of the embryonic stem cells in culture at any given time, which points to the fact that it has a tight regulatory system. Furthermore, ZSCAN4, if included in the reprogramming cocktail along with core reprogramming factors, increases the reprogramming efficiency and results in better quality, genetically stable induced pluripotent stem cells. Also, it is reported to have a role in promoting cancer stem cell phenotype and can prospectively be used as a marker for the same. In this review, the multifaceted role of ZSCAN4 in embryonic development, embryonic stem cells, induced pluripotent stem cells, cancer, and germ cells are discussed comprehensively.

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Research on telomeres in the fields of ecology and evolution has been rapidly expanding over the last two decades. This has resulted in the formulation of a multitude of, often name-given, hypotheses related to the associations between telomeres and life-history traits or fitness-facilitating processes (and the mechanisms underlying them). However, the differences (or similarities) between the various hypotheses, which can originate from different research fields, are often not obvious. Our aim here is therefore to give an overview of the hypotheses that are of interest in ecology and evolution and to provide two frameworks that help discriminate among them. We group the hypotheses (i) based on their association with different research questions, and (ii) using a hierarchical approach that builds on the assumptions they make, such as about causality of telomere length/shortening and/or the proposed functional consequences of telomere shortening on organism performance. Both our frameworks show that there exist parallel lines of thoughts in different research fields. Moreover, they also clearly illustrate that there are in many cases competing hypotheses within clusters, and that some of these even have contradictory assumptions and/or predictions. We also touch upon two topics in telomere research that would benefit from further conceptualization. This review should help researchers, both those familiar with and those new to the subject, to identify future avenues of research.

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Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5' mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation.

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It is now widely accepted that mitochondrial biogenesis is inhibited in most cancer cells. Interestingly, one of the possible exceptions is colorectal cancer (CRC), in which the content of mitochondria has been found to be higher than in normal colon mucosa. However, to date, the causes and effects of this phenomenon are still unclear. In the present study, we systematically investigated the functional role of mitochondrial single-strand DNA binding protein (mtSSB), a key molecule in the regulation of mitochondrial DNA (mtDNA) replication, in the mitochondrial biogenesis and CRC cell growth. Our results demonstrated that mtSSB was frequently upregulated in CRC tissues and that upregulated mtSSB was associated with poor prognosis in CRC patients. Furthermore, overexpression of mtSSB promoted CRC cell growth in vitro by regulating cell proliferation. The in vivo assay confirmed these results, indicating that the forced expression of mtSSB significantly increases the growth capacity of xenograft tumors. Mechanistically, the survival advantage conferred by mtSSB was primarily caused by increased mitochondrial biogenesis and subsequent ROS production, which induced telomerase reverse transcriptase (TERT) expression and telomere elongation via Akt/mTOR pathway in CRC cells. In addition, FOXP1, a member of the forkhead box family, was identified as a new transcription factor for mtSSB. Moreover, our results also demonstrate that proinflammatory IL-6/STAT3 signaling facilitates mtSSB expression and CRC cell proliferation via inducing FOXP1 expression. Collectively, our findings demonstrate that mtSSB induced by inflammation plays a critical role in the regulation of mitochondrial biogenesis, telomerase activation, and subsequent CRC proliferation, providing a strong evidence for mtSSB as drug target in CRC treatment.

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Telomere length homeostasis, critical for chromosomal integrity and genome stability, is controlled by intricate molecular regulatory machinery that includes epigenetic modifications. Here, we examine site-specific and spatiotemporal alteration of the subtelomeric methylation of CpG islands using optogenetic tools to understand the epigenetic regulatory mechanisms of telomere length maintenance. Human DNA methyltransferase3A (DNMT3A) were assembled selectively at chromosome ends by fusion to cryptochrome 2 protein (CRY2) and its interacting complement, the basic helix loop helix protein-1 (CIB1). CIB1 was fused to the telomere-associated protein telomere repeat binding factor-1 (TRF1), which localized the protein complex DNMT3A-CRY2 at telomeric regions upon excitation by blue-light monitored by single-molecule fluorescence analyses. Increased methylation was achieved selectively at subtelomeric CpG sites on the six examined chromosome ends specifically after blue-light activation, which resulted in progressive increase in telomere length over three generations of HeLa cell replications. The modular design of the fusion constructs presented here allows for the selective substitution of other chromatin modifying enzymes and for loci-specific targeting to regulate the epigenetic pathways at telomeres and other selected genomic regions of interest.

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Alternative Lengthening of Telomeres (ALT) mechanisms allow telomerase-negative immortal cells to buffer replicative telomere shortening. ALT is naturally active in a number of human cancers and might be selected upon telomerase inactivation. ALT is thought to operate through homologous recombination (HR) occurring between telomeric repeats from independent chromosome ends. Indeed, suppression of a number of HR factors impairs ALT cell proliferation. Yet, how HR is initiated at ALT telomeres remains elusive. Mounting evidence suggests that the long noncoding telomeric RNA TERRA renders ALT telomeres recombinogenic by forming RNA:DNA hybrids with the telomeric C-rich strand. TERRA and telomeric hybrids act in concert with a number of other factors, including the RNA endoribonuclease RNaseH1 and the single stranded DNA binding protein RPA. The functional interaction network built upon these different players seems indispensable for ALT telomere maintenance, and digging into the molecular details of this previously unappreciated network might open the way to novel avenues for cancer treatments.

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BACKGROUND: Glioma is the most devastating type of malignant brain tumors in adults. Genetic factors play important roles in the pathogenesis of glioma. In recent years, some studies found that there were significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility, however, the results were controversial. The aim of this study was to obtain a more exact estimation of the association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma through a meta-analysis. METHODS: The meta-analysis included 19 published case-control studies involving 8541 cases and 14226 controls. The included papers were searched from PubMed and Embase database. Odds ratio (OR) with 95% confidence interval (95% CI) were used to evaluate the association of regulator of telomere elongation helicase 1 rs6010620 polymorphism with glioma. RESULTS: A significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility was observed for GG vs. AA+AG (OR=1.28, 95% CI=1.14-1.43) and G vs. A (OR=1.07, 95% CI=1.03-1.10). Further subgroup analysis based on ethnicity showed similar results in Asians and Caucasians. In the subgroup analysis of source of control, a significant association between the G allele and glioma susceptibility were found in population-based group and hospital-based group. CONCLUSIONS: The meta-analysis suggested that regulator of telomere elongation helicase 1 rs6010620 polymorphism was a risk factor for glioma. And this study also suggested that rs6010620 GG genotype and G allele may be indicators for the risk of glioma.

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Fluorescence microscopy can be used to assess the dynamic localization and intensity of single entities in vitro or in living cells. It has been applied with aplomb to many different cellular processes and has significantly enlightened our understanding of the heterogeneity and complexity of biological systems. Recently, high-resolution fluorescence microscopy has been brought to bear on telomeres, leading to new insights into telomere spatial organization and accessibility, and into the mechanistic nuances of telomere elongation. We provide a snapshot of some of these recent advances with a focus on mammalian systems, and show how three-dimensional, time-lapse microscopy and single-molecule fluorescence shine a new light on the end of the chromosome.

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Telomeres are DNA-protein structures that form a protective cap on chromosome ends. As such, they prevent the natural ends of linear chromosomes from being subjected to DNA repair activities that would result in telomere fusion, degradation, or recombination. Both the DNA and protein components of the telomere are required for this essential function, because insufficient telomeric DNA length, loss of the terminal telomeric DNA structure, or deficiency of key telomere-associated factors may elicit a DNA damage response and result in cellular senescence or apoptosis. In the setting of failed checkpoint mechanisms, such DNA-protein defects can also lead to genomic instability through telomere fusions or recombination. Thus, as shown in both model systems and in humans, defects in telomere biology are implicated in cellular and organismal aging as well as in tumorigenesis. Bone marrow failure and malignancy are 2 life-threatening disease manifestations in the inherited telomere biology disorder dyskeratosis congenita. We provide an overview of basic telomere structure and maintenance. We outline the telomere biology defects observed in dyskeratosis congenita, focusing on recent discoveries in this field. Last, we review the evidence of how telomere biology may impact sporadic aplastic anemia and the risk for various cancers.

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