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.

The telomere is a functional domain of the chromosome, located at the extreme ends, and is essential for normal chromosome stability. Chromosomes lacking telomeres are inherited improperly, and mutations in the telomeric repeat sequences are thought to lead to senescence and possibly to cancer. The molecular mechanisms maintaining chromosomes by telomeres, however, have been unclear. Results recently reported by Kirk et al.(1) offer an insight into new telomerase function. They have identified a novel telomerase mutation that blocks sister (...) chromatid separation in mitosis. (shrink)

Human telomerase progressively emerged as a multifaceted ribonucleoprotein complex with additional functions beyond telomeric repeat synthesis. Both the hTERT catalytic subunit and the hTR long non‐coding RNA (lncRNA) subunit are engaged in highly regulated cellular pathways that, together, contribute to cell fitness and protection against apoptosis. We recently described a new role for hTR in regulating the abundance of replication protein A at telomeres, adding to the growing repertoire of hTR’s functions. Here, we focus on the non‐canonical roles of (...) hTR and discuss them in the context of the structural elements of the lncRNA. We propose that some functions of hTR may compete amongst each other through distinct interactions with its partners, proteins or mRNAs. We postulate that hTR’s non‐canonical functions may be highly relevant in the context of normal somatic cells that naturally silence hTERT gene, while keeping hTR expression. (shrink)

Telomeres, the ends of chromosomes, shorten with each cell division. To expand their replicative potential, various cell types use the ribonucleoprotein telomerase, which lengthens telomeres by its reverse transcriptase activity. Because of its ability to immortalize cancer cells, telomerase also plays a significant role in tumor growth. However, in recent years, a wide variety of non‐canonical effects of telomerase that are independent of telomere lengthening have been discovered, and even the notion that telomerase is restricted to (...) very few cell types has been questioned. These effects also seem to be important in carcinogenesis and might explain the tumor‐promoting effects of telomerase independently of telomere elongation. Here, the current understanding of the extratelomeric roles of telomerase and their physiological and pathological significance is reviewed. BioEssays 30:728–732, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Whereas telomeres protect terminal ends of linear chromosomes, telomerases identify natural chromosome ends, which differ from broken DNA and replicate telomeres. Although telomeres play a crucial role in the linear chromosome organization of eukaryotic cells, their molecular syntax most probably descended from an ancient retroviral competence. This indicates an early retroviral colonization of large double-stranded DNA viruses, which are putative ancestors of the eukaryotic nucleus. This contribution demonstrates an advantage of the biosemiotic approach towards our evolutionary understanding of telomeres, telomerases, (...) other reverse transcriptases and mobile elements. Their role in genetic/genomic content organization and maintenance is no longer viewed as an object of randomly derived alterations (mutations) but as a highly sophisticated hierarchy of regulatory networks organized and coordinated by natural genome-editing competences of viruses. (shrink)

Dyskeratosis congenita is a rare skin and bone marrow failure syndrome caused by defective telomere maintenance in stem cells. The major X‐linked form of the disease is due to mutations in a nucleolar protein, dyskerin, that is part of small nucleolar ribonucleoprotein particles that are involved in processing ribosomal RNA. It is also found in the telomerase complex, pointing to an unexpected link between these two processes. An autosomal dominant form is due to mutations in the RNA component of (...) telomerase (hTR). Patients with this form of the disease are more severely affected in later generations that carry the mutations, possibly due to the inheritance of shortened telomeres, disguising the inherited nature of the disease in some cases classified as aplastic anemia. Because of the importance of telomerase in tumour formation and aging, study of this disease may provide important clues about these fundamental processes. BioEssays 25:126–133, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Meditation involves psychophysical training which can result in a range of benefits including creating a calm mind and increasing self-awareness, relaxation, and tranquility. Increasing evidence, mostly based on short-term focused interventions, suggests that meditation-based activities may also have favorable effects on physical wellbeing including cellular aging. Hence, the aim of this study was to investigate if continued practice of meditation benefited quality of life, state of mindfulness, and plasma telomerase level in healthy adults. 30 long-term and skilled meditators were (...) recruited from meditation centers in different parts of the island following a two-tier screening process of 70 eligible participants and 30 age- and gender-matched healthy non-meditators were recruited from the community. Mindfulness level and the quality of life were measured using the Five Facet Mindfulness Questionnaire and Quality of Life Questionnaire, respectively, while the levels of plasma telomerase enzyme were measured using Enzyme-Linked Immunosorbent Assay. Skilled meditators had a better mindfulness level and quality of life than those in the comparison group. Similarly, higher plasma telomerase levels were observed in skilled meditators compared to non-meditators. Trait mindfulness level and plasma telomerase level showed a significant relationship with the duration of meditation practice. Regression analysis indicated that trait mindfulness level significantly predicts the plasma telomerase level. The findings of this comparative study add to the evidence on sustained benefits of meditation on wellbeing and healthy aging and supports incorporating meditation-based activities into lifestyle practices. (shrink)

Telomerase is a cellular reverse transcriptase responsible for telomere maintenance in most organisms. It does so by adding telomere repeats onto pre‐existing ends using an integral RNA component as template. Compared to “prototypical” reverse transcriptases, telomerase is unique in being able to repetitively copy a short templating RNA segment, thus adding multiple copies of the repeat to the DNA substrate following a single binding event. This uniquely processive property hints at the intricate conformational alterations that the enzyme must (...) choreograph during its reaction cycles. Recent studies have identified distinct structural elements within both the RNA and protein components of telomerase that modulate enzyme processivity. Pharmacological and genetic analysis suggest that telomerase processivity is a significant determinant of telomere length. Because telomere maintenance and the lack thereof have been linked to tumor progression and aging, further investigation of telomerase processivity may lead to novel medical intervention strategies. BioEssays 26:955–962, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Telomeres are protective caps for chromosome ends that are essential for genome stability. Broken chromosomes missing a telomere will not be maintained unless the chromosome is ‘healed’ with the formation of a new telomere. Chromosome healing can be a programmed event following developmentally regulated chromosome fragmentation, or it may occur spontaneously when a chromosome is accidentally broken. In this article we discuss the consequences of telomere loss and the possible mechanisms that the enzyme telomerase employs to form telomeres de (...) novo on broken chromosome ends. (shrink)

Linear chromosomes shorten in every round of replication. In Drosophila, telomere‐specialized long interspersed retrotransposable elements (LINEs) belonging to the jockey clade offset this shortening by forming head‐to‐tail arrays at Drosophila telomere ends. As such, these telomeric LINEs have been considered adaptive symbionts of the genome, protecting it from premature decay, particularly as Drosophila lacks a conventional telomerase holoenzyme. However, as reviewed here, recent work reveals a high degree of variation and turnover in the telomere‐specialized LINE lineages across Drosophila. There (...) appears to be no absolute requirement for LINE activity to maintain telomeres in flies, hence the suggestion that the telomere‐specialized LINEs may instead be neutral or in conflict with the host, rather than adaptive. (shrink)

Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA‐protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non‐depressed persons, which may contribute to the observed unfavorable somatic health outcomes in the depressed (...) population. Some small‐scale preliminary studies raise the possibility that behavioral or pharmacological interventions may either slow down or else reverse this accelerated telomere shortening, possibly through increasing the activity of the telomere‐lengthening enzyme telomerase. This paper covers the current state of evidence in the relationship between depression and the telomere‐telomerase system and debates whether depression‐related cellular aging should be considered a reversible process or permanent damage. (shrink)

Recent advances in human genetics suggest that it may become possible to genetically manipulate telomerase and embryonic stem cells to alter the mechanisms of aging and extend the human life span. But a life span significantly longer than the present norm would be undesirable because it would severely weaken the connections between past‐ and future‐oriented mental states and in turn the psychological grounds for personal identity and prudential concern for our future selves. In addition, the collective effects of longer (...) lives might lower the quality of life for all people. These two problems provide reasons against genetic manipulation of cells to alter the length of the human life span. (shrink)

The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of “difficult to repair” lesions such as double‐strand breaks without a repair template and eroded telomeres in telomerase‐deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure‐forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus to (...) the NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC‐facilitated repair. (shrink)

In this study a combination of computer tools for coupling and virtual screening is detailed, in 108 active molecules and 3620 decoys to find stabilizers for G quadruplex. To have more precise results, combinations of coupling programs with fifteen energy scoring functions were applied. The validation and evaluation of the metrics was done with the CompScore genetic algorithm. The results showed an increase in BEDROC and EF of 50% compared to other strategies, as well as reflecting early recognition of active (...) molecules. From these results it is possible to work with the molecules that showed a good early recognition and evaluate their effect as G4 stabilizers. This ensures more efficient and accurate results in the preclinical stage for the development of anticancer drugs. Keywords: Enrichment metrics; telomere; G quadruplex ; CompScore. References [1]M. Porru, P. Zizza, M. Franceschin, C. Leonetti and A. Biroccio. «EMICORON: A multi-targeting G4 ligand with a promising preclinical profile» 2017. Biochimica et Biophysica Acta - General Subjects, 1861, 1362–1370. [Online]. Available: https://doi.org/10.1007/s00294-018-0836-6. [2]K. Tomita. «How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis». Current Genetics, 64, 1177–1181. 2018. [Online]. Available: https://doi.org/10.1016/j.bbagen. 2016.11.010. [3]M. Jafri, S. Ansari, M. Alqahtani and J. Shay. «Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine., 2016. [Online]. Available: https://doi.org/10.3390/ijms19020482. [4]J. Huppert and S. Balasubramanian. «G-quadruplexes in promoters throughout the human genome». 35, 406–413. 2007. [Online]. Available: https://doi.org/10.1016/j.bbapap.2017.06.012. [5]S. Joy, Vijayakumar, S. Choi and H. Sunhye. «Role of computer-aided drug design in modern drug discovery». Archives of Pharmacal Research. 2015. [Online]. Available: https://doi.org/10.1007/s12272-015-0640-5. [6]S. Asamitsu, S. Obata, Z. Yu, T. Bando and H. Sugiyama. «Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy». Molecules, 24, 429. 2019. [En línea]. Available: https://doi.org/10.3390/molecules24030429. [7]R. Monsen and J. Trent. «Biochimie G-quadruplex virtual drug screening : A review». Biochimie, 152, 134–148. 2018. [Online]. Available: https://doi.org/10.1039/c9cc06748e. [8]J. Beauvarlet, P. Bensadoun, E. Darbo, G. Labrunie, E. Richard, I. Draskovic and M. Djavaheri-mergny. «Modulation of the ATM / autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells». 1–18. 2019. [Online]. Available: https://doi.org/10.1093/nar/gkz095. [9].Z. Crees, J. Girard, Z. Rios, G. Botting, K. Harrington and C. Shearrow. « Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy».2014. [Online]. Available: https://doi.org/10.2174/1381612820666140630100702. [10].M. Meier, A. Moya-torres, N. Krahn, M. Mcdougall, L. Orriss, E. Mcrae and T. Patel. «Structure and hydrodynamics of a DNA Gquadruplex with a cytosine bulge»., 1–13. 2018. [Online]. Available: https://doi.org/10.1093/nar/gky307. (shrink)

We propose that the sudden emergence of metazoans during the Cambrian was due to the appearance of a complex genome architecture that was capable of computing. In turn, this made defining recursive functions possible. The underlying molecular changes that occurred in tandem were driven by the increased probability of maintaining duplicated DNA fragments in the metazoan genome. In our model, an increase in telomeric units, in conjunction with a telomerase-negative state and consequent telomere shortening, generated a reference point equivalent (...) to a non-reversible counting mechanism. (shrink)

The replication of linear chromosome DNA by DNA polymerase leads to the loss of terminal sequences, in the absence of a special mechanism to maintain ends or telomeres. This mechanism is known to consist of short terminal repeats and the enzyme telomerase, which contains RNA complementary to the DNA repeats. There is evidence that telomeric DNA continually decreases in size in the absence of telomerase, and this is followed by cellular senescence. Immortalisation of somatic cells is accompanied, at (...) least in some cases, by acquisition of telomerase activity. The cloning of DNA coding for the RNA component of telomerase has opened up some new experimental approaches, including the study of telomerases with mutant RNA(1,2). The telomere theory of cellular senescence appears to provide a molecular basis for the ‘Hayflick limit’ to human fibroblast growth. However the telomeres and behaviour of primary mouse cells are anomolous(3), and many immortalised human cell lines lack normal telomerase activity(4). These exceptions are not easily accommodated in the telomere theory. (shrink)

DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric (...) regions that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long‐read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature. (shrink)

The concept of a G‐quartet, a unique structural arrangement intrinsic to guanine‐rich DNA, was first introduced by Gellert and colleagues1 over 40 years ago. For decades, it has been uncertain whether the G‐quartet and the structure that it gives rise to, the G‐quadruplex, are purely in vitro phenomena. Nevertheless, the presence of signature G‐rich motifs in the eukaryotic genome, and the plethora of proteins that bind to, modify or resolve this nucleic acid structure in vitro have provided circumstantial evidence for (...) its physiological relevance. More recently, direct visualisation of G‐quadruplex DNA at native telomeres was achieved, bolstering the evidence for its existence in the cell. Furthermore, G‐quadruplex folded telomeric DNA has been found to perturb telomere function and to impede the action of telomerase, an enzyme overexpressed in >85% of human cancers, hence opening up a novel avenue for cancer therapy in the form of G‐quadruplex stabilising agents. BioEssays 29: 155–165, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Pluripotent stem cells have gained special attraction because of their almost unlimited proliferation and differentiation capacity in vitro. These properties substantiate the potential of pluripotent stem cells in basic research and regenerative medicine. Here three types of in vitro‐cultured pluripotent stem cells (embryonic carcinoma, embryonic stem and induced pluripotent stem cells) are compared in their historical context with respect to their different origin and properties. It became evident that tumourigenicity is an inherent property of pluripotent cells based on p53 down‐regulation, (...) expression of tumour‐related genes and high telomerase activity that allow unlimited proliferation. In addition, culture‐adapted genetic and epigenetic changes may induce tumourigenicity of pluripotent cells. The use of stem cells in regenerative medicine, however, requires non‐malignant cell types and strategies that circumvent stages of malignancy. Reprogramming strategies of adult somatic cells that avoid the tumourigenic state of pluripotency may offer alternatives for future biomedical application. (shrink)

Poly(ADP‐ribosyl)ation is a post‐translational modification occurring in the nucleus. The most abundant and best‐characterized enzyme catalyzing this reaction, poly(ADP‐ribose) polymerase 1 (PARP1), participates in fundamental nuclear events. The enzyme functions as molecular “nick sensor”. It binds with high affinity to DNA single‐strand breaks resulting in the initiation of its catalytic activity. Activated PARP1 promotes base excision repair. In addition, PARP1 modifies several transcription factors and thereby precludes their binding to DNA. We propose that a major function of PARP1 includes the (...) silencing of transcription preventing expression of damaged genes. Concomitant stimulation of DNA repair suggests that PARP1 acts as a switch between transcription and DNA repair. Another PARP‐type enzyme, tankyrase, is involved in the regulation of telomere elongation. Tankyrase modifies a telomere‐associated protein and thereby prevents it masking telomeric repeats providing access of telomerase for telomere elongation. Therefore, poly(ADP‐ribosyl)ation reactions may act as molecular switches in DNA metabolism. BioEssays 23:543–548, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The structures of specific chromosome regions, centromeres and telomeres, present a number of puzzles. As functions performed by these regions are ubiquitous and essential, their DNA, proteins and chromatin structure are expected to be conserved. Recent studies of centromeric DNA from human, Drosophila and plant species have demonstrated that a hidden universal centromere‐specific sequence is highly unlikely. The DNA of telomeres is more conserved consisting of a tandemly repeated 6–8 bp Arabidopsis‐like sequence in a majority of organisms as diverse as (...) protozoan, fungi, mammals and plants. However, there are alternatives to short DNA repeats at the ends of chromosomes and for telomere elongation by telomerase. Here we focus on the similarities and diversity that exist among the structural elements, DNA sequences and proteins, that make up terminal domains (telomeres and subtelomeres), and how organisms use these in different ways to fulfil the functions of end‐replication and end‐protection. BioEssays 27:685–697, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Mammalian telomeres have evolved safeguards to prevent their recognition as DNA double‐stranded breaks by suppressing the activation of various DNA sensing and repair proteins. We have shown that the telomere‐binding proteins TRF2 and RAP1 cooperate to prevent telomeres from undergoing aberrant homology‐directed recombination by mediating t‐loop protection. Our recent findings also suggest that mammalian telomere‐binding proteins interact with the nuclear envelope to maintain chromosome stability. RAP1 interacts with nuclear lamins through KU70/KU80, and disruption of RAP1 and TRF2 function result in (...) nuclear envelope rupture, promoting telomere‐telomere recombination to form structures termed ultrabright telomeres. In this review, we discuss the importance of the interactions between shelterin components and the nuclear envelope to maintain telomere homeostasis and genome stability. (shrink)

Drosophila telomeres comprise DNA sequences that differ dramatically from those of other eukaryotes. Telomere functions, however, are similar to those found in telomerase‐based telomeres, even though the underlying mechanisms may differ. Drosophila telomeres use arrays of retrotransposons to maintain chromosome length, while nearly all other eukaryotes rely on telomerase‐generated short repeats. Regardless of the DNA sequence, several end‐binding proteins are evolutionarily conserved. Away from the end, the Drosophila telomeric and subtelomeric DNA sequences are complexed with unique combinations of (...) proteins that also modulate chromatin structure elsewhere in the genome. Maintaining and regulating the transcriptional activity of the telomeric retrotransposons in Drosophila requires specific chromatin structures and, while telomeric silencing spreads from the terminal repeats in yeast, the source of telomeric silencing in Drosophila is the subterminal arrays. However, the subterminal arrays in both species may be involved in telomere–telomere associations and/or communication. BioEssays 30:25–37, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Although early‐life adversity has been associated with negative consequences during adulthood, growing evidence shows that such adversity can also lead to subsequent stress resilience and positive fitness outcomes. Telomere dynamics are relevant in this context because of the link with developmental conditions and longevity. However, few studies have assessed whether the effects of early‐life adversity on developmental telomere dynamics may relate to adult telomere dynamics. We propose that the potential links between early‐life adversity and adult telomere dynamics could be driven (...) by developmental constraints (the Constraint hypothesis), by the nature/severity of developmental adversity (the Resilience hypothesis), or by developmental‐mediated changes in individual life‐history strategies (the Pace of Life hypothesis). We discuss these non‐mutually exclusive hypotheses, explore future research directions, and propose specific studies to test these hypotheses. Our article aims to expand our understanding of the evolutionary role of developmental conditions on adult telomere dynamics, stress resilience and ageing. (shrink)