Schmidt J.C., Zaug A.J., Kufer R., Cech T.R. Kachuri L., Helby J., Bojesen S.E., Christiani D.C., Su L., Wu X., Tardon A., Fernandez-Tardon G., Field J.K., Davies M.P., et al. Njajou O.T., Cawthon R.M., Damcott C.M., Wu S.H., Ott S., Garant M.J., Blackburn E.H., Mitchell B.D., Shuldiner A.R., Hsueh W.C. Telomere length is paternally inherited and is associated with parental lifespan. Breakthrough to halt premature aging of cells Study identifies potential drug treatments for telomere diseases By Capping decades of research, a new study may offer a breakthrough in treating dyskeratosis congenita and other so-called telomere diseases, in which cells age prematurely. DNA polymerase Pol with a single RNA primer initiates the synthesis of a new strand in 5 to 3 direction towards replication fork, which is subsequently replaced by Pol for further elongation, forming the leading strand [86,87]. Marcand S., Brevet V., Mann C., Gilson E. Cell cycle restriction of telomere elongation. The telomeres, organized within tightly packed histone octamer composed nucleosomes (Figure 2), are stabilized through specific proteinprotein and proteinDNA interactions between shelterin subunits and tandem repeat sequences [25,27]. Stern J.L., Theodorescu D., Vogelstein B., Papadopoulos N., Cech T.R. Mason-Osann E., Dai A., Floro J., Lock Y.J., Reiss M., Gali H., Matschulat A., Labadorf A., Flynn R.L. The ETM model proposes that T-oligos accumulate in the nucleus and are recognized as damaged telomeres, initiating a DDR mechanism similar to those occurring during excessive telomere shortening [250]. Gu P., Min J.N., Wang Y., Huang C., Peng T., Chai W., Chang S. Ctc1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. a SNP, single nucleotide polymorphism. Increased copy number of the tert and terc telomerase subunit genes in cancer cells. De Meyer T., Vandepitte K., Denil S., De Buyzere M.L., Rietzschel E.R., Bekaert S. A non-genetic, epigenetic-like mechanism of telomere length inheritance? Barthel F.P., Wei W., Tang M., Martinez-Ledesma E., Hu X., Amin S.B., Akdemir K.C., Seth S., Song X., Wang Q., et al. Lengthening and protecting your telomeres may be the answer. Shelterin and subtelomeric DNA sequences control nucleosome maintenance and genome stability. Mefford H.C., Trask B.J. Normal human cells in a culture stop dividing after 40 to 60 passages, a phenomenon first observed by Leonard Hayflick and eponymously called the Hayflick limit [89,92]. A number of telomere length associated genetic loci associated have been identified through linkage analysis and GWAS [178,179,180,181,182,183,184,185,186]. The genomic region on chromosome 5 at 5p15.33, harboring TERT and cleft lip and palate associated transmembrane 1-like protein (CLPTM1L) genes, has been reported to contain several independent cancer susceptibility loci [194,206,207]. sharing sensitive information, make sure youre on a federal Rankin A.M., Forman L., Sarkar S., Faller D.V. It all comes together at the ends: Telomerase structure, function, and biogenesis. Subtelomers (green) represent regions of genes interspersed within repeat elements and interstitial telomeric sequence (red arrow); (B) shelterin complex, the G-tail folds back into the duplex DNA to form the t-loop; (C) G-quadruplex structure, intramolecular G-quadruplex (left) built from G-quartets that are formed through cyclic Hoogsten hydrogen-bonding arrangement of four guanines with each other with G-tetrad structure on the right. Lond. It seems that telomere length that depends on many different factors (including telomerase activity but also genetic factors, a hormonal profile . Huang F.W., Hodis E., Xu M.J., Kryukov G.V., Chin L., Garraway L.A. Tert promoter status and gene copy number gains: Effect on tert expression and association with prognosis in breast cancer. Holohan B., Wright W.E., Shay J.W. Asamitsu S., Obata S., Yu Z., Bando T., Sugiyama H. Recent progress of targeted g-quadruplex-preferred ligands toward cancer therapy. Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma. Campa D., Matarazzi M., Greenhalf W., Bijlsma M., Saum K.U., Pasquali C., van Laarhoven H., Szentesi A., Federici F., Vodicka P., et al. The heterochromatin-associated marks include H4K20me3, H3K9me3, and H3K27me3. This process of telemeres shortening during this span is referred to as the hayflick limit. In vitro biochemical analysis has shown that CST unfolds G-quadruplex structures to facilitate replication through telomeres [61,62]. Most of cancers rely on telomerase to extend and maintain telomeres, but 4-11% of cancers use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). Fine-mapping analysis of the region in GWAS from four cancers identified an SNP, rs36115365, with a functional role in regulating TERT expression, which is located in-between the 5end of TERT and 3 end of CLPTM1L, with active histone modification marks and multiple transcription factor binding sites [208]. Baird D.M. Tennen R.I., Bua D.J., Wright W.E., Chua K.F. Vasa-Nicotera M., Brouilette S., Mangino M., Thompson J.R., Braund P., Clemitson J.R., Mason A., Bodycote C.L., Raleigh S.M., Louis E., et al. Telomerase expression by aberrant methylation of the tert promoter in melanoma arising in giant congenital nevi. Numerous studies have found that what we eat has a significant role in telomere length and health and the rate at which the telomeres shorten. Benetos A., Kark J.D., Susser E., Kimura M., Sinnreich R., Chen W., Steenstrup T., Christensen K., Herbig U., von Bornemann Hjelmborg J., et al. Shay J.W., Wright W.E. Telomeric rnas are essential to maintain telomeres. Telomere length and survival in primary cutaneous melanoma patients. Iles M.M., Bishop D.T., Taylor J.C., Hayward N.K., Brossard M., Cust A.E., Dunning A.M., Lee J.E., Moses E.K., Akslen L.A., et al. T-oligos induce DDR mechanism via two potential modes, the shelterin dissociation model (SDM) and the exposed telomere mimicry model (ETM). HHS Vulnerability Disclosure, Help Mannan T., Ahmed S., Akhtar E., Ahsan K.B., Haq A., Kippler M., Vahter M., Raqib R. Associations of arsenic exposure with telomere length and naive t cells in childhood-a birth cohort study. Lei M., Podell E.R., Cech T.R. getty By 1990, scientists knew that telomeres are repetitive DNA sequences found at the tips of the long strings of DNA that are chromosomes. Telomeres and telomerase-based therapies are emerging as prospective cancer treatment strategies [250]. A prospective study of telomere length and the risk of skin cancer. Lachner M., OCarroll D., Rea S., Mechtler K., Jenuwein T. Methylation of histone h3 lysine 9 creates a binding site for hp1 proteins. Which means folate may lengthen and protect telomeres. Arnoult N., Karlseder J. Telomere length in white blood cell DNA and lung cancer: A pooled analysis of three prospective cohorts. "The genetic basis of aging is complex, and it is likely that both cellular . Srinivas N., Rachakonda S., Hielscher T., Calderazzo S., Rudnai P., Gurzau E., Koppova K., Fletcher T., Kumar R. Telomere length, arsenic exposure and risk of basal cell carcinoma of skin. TRF1 and TRF2 contain a TRF homology (TRFH) domain that mediates homodimerization and a Myb-type domain that specifically binds to the telomere duplex [40,41,42]. Telomere structure and telomerase in health and disease (review). Treatment with T-oligos in vitro has been shown to be effective in reducing viability and tumor growth in several cancers, including melanoma, prostate, ovarian, lung, breast, and colorectal cancer [250,254,255,256,257,258]. The loss of ATRX and DAXX due to mutations leads to a repressed heterochromatin state that activates recombination and initiation of ALT [154,161]. Kalathiya U., Padariya M., Baginski M. The structurally similar trfh domain of trf1 and trf2 dimers shows distinct behaviour towards tin2. DDB1 functions as a binding partner for the transcription factor E2F1, a member of the E2F family of transcription factors that regulate cell proliferation and telomerase activity [201,202]. Martinez P., Thanasoula M., Carlos A.R., Gomez-Lopez G., Tejera A.M., Schoeftner S., Dominguez O., Pisano D.G., Tarsounas M., Blasco M.A. Exposure to environmental radionuclides associates with tissue-specific impacts on telomerase expression and telomere length. Although the G-quadruplex structure in vivo has been observed by nuclear magnetic resonance, its biological function remains unknown [20,22]. McNally E.J., Luncsford P.J., Armanios M. Long telomeres and cancer risk: The price of cellular immortality. Mangino M., Brouilette S., Braund P., Tirmizi N., Vasa-Nicotera M., Thompson J.R., Samani N.J. A regulatory snp of the bicd1 gene contributes to telomere length variation in humans. Lin C., Yang D. Human telomeric g-quadruplex structures and g-quadruplex-interactive compounds. Several other factors that influence telomere length include oxidative stress, inflammation, lifestyle factors, physiological stress, and exposure to carcinogens [210,211,212]. The depletion of CTCF or Rad21 results in reduced binding of TRF1 and TRF2 to telomeres [200]. 8600 Rockville Pike Following a healthy Mediterranean-style diet and eating more fibrous foods can help lengthen your telomeres. Subtelomeres are transcriptionally active chromatin regions (Figure 1A) between main chromosomal sequences and telomeres [71]. A specific region within the THOR, from 668 to 577 bp from the ATG start site (Chr5: 1,295,6811,295,772), was shown to be hypomethylated in tumor-derived cell lines (Figure 7B) with TERT promoter mutations compared to those without mutations [146]. Adapted from [123,146,147]. Adapted from [34]. Telomeres, intrinsically unstable fragile sites, are stabilized through binding with so-called shelterin complex proteins [12,15,16]. Chow T.T., Shi X., Wei J.H., Guan J., Stadler G., Huang B., Blackburn E.H. Local enrichment of hp1alpha at telomeres alters their structure and regulation of telomere protection. In a study on basal cell carcinoma, a reversal of the effect was reported, where arsenic exposure and short telomeres were shown to synergistically increase the risk in a dose-dependent manner [249]. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Lin J., Countryman P., Buncher N., Kaur P., Longjiang E., Zhang Y., Gibson G., You C., Watkins S.C., Piehler J., et al. Mammalian cst averts replication failure by preventing g-quadruplex accumulation. Genome-wide meta-analysis points to ctc1 and znf676 as genes regulating telomere homeostasis in humans. Erdel F., Kratz K., Willcox S., Griffith J.D., Greene E.C., de Lange T. Telomere recognition and assembly mechanism of mammalian shelterin. Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: The long life family study. TRF1 and TRF2 that exist as homodimers bind to the double-stranded DNA, and POT1 binds to the single-stranded 3 G-overhang [39,40]. Accessibility TRF1 and TRF2 bind the double-stranded DNA; POT1 binds the single-stranded 3 G-overhang. J. Hockemeyer D., Palm W., Else T., Daniels J.P., Takai K.K., Ye J.Z., Keegan C.E., de Lange T., Hammer G.D. Telomere protection by mammalian pot1 requires interaction with tpp1. Riethman H. Human subtelomeric copy number variations. Therapeutic inhibition of trf1 impairs the growth of p53-deficient k-rasg12v-induced lung cancer by induction of telomeric DNA damage. Telomerase is upregulated in tumors from over 90% of cancers; in 10% to 15% of tumors, telomeres are elongated through a homologous recombination-based alternative lengthening of telomeres (ALT) [97]. The association between telomere length and environmental, occupational, and health risk factors has been reported in several cross-sectional epidemiological studies [210,211,212]. A biological role for TIN2 dependent on TPP1-POT1 has been suggested where its binding stabilizes the complex and promotes telomere processivity [53]. The model of repeat-addition processivity involves the addition of telomere repeats by the holoenzyme in successive steps without primer dissociation and requires several elements [12]. The subtelomeric region constitutes two major zones: polymorphic patchworks of inter-chromosomal segmental duplication region and a chromosome specific non-duplicated region [72,73]. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies. Introduction If you could zoom in and look at the DNA on the tip of one of your chromosomes, what would you see? Marcand S., Brevet V., Gilson E. Progressive cis-inhibition of telomerase upon telomere elongation. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with tert expression. Lau L.M., Dagg R.A., Henson J.D., Au A.Y., Royds J.A., Reddel R.R. Shelterin complex comprises of six protein subunits [13]. Rai R., Chen Y., Lei M., Chang S. Trf2-rap1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Telomeres are, in general, associated with three types of proteins that include nucleosomes, shelterin complex, and chromosomal transcription factors [13,25,26]. Alternative lengthening of telomeres renders cancer cells hypersensitive to atr inhibitors. Mazzolini R., Gonzalez N., Garcia-Garijo A., Millanes-Romero A., Peiro S., Smith S., Garcia de Herreros A., Canudas S. Snail1 transcription factor controls telomere transcription and integrity. RNA primers are degraded and the gaps filled by Pol followed by ligation of discontinuous fragments. Martinez P., Blasco M.A. The enzyme telomerase has been shown to bind to and extend the length of telomeres. Off. Hu C., Rai R., Huang C., Broton C., Long J., Xu Y., Xue J., Lei M., Chang S., Chen Y. They ranged in age from 7 to . Armanios M., Blackburn E.H. Dynamic DNA binding, junction recognition and g4 melting activity underlie the telomeric and genome-wide roles of human cst. Box J.A., Bunch J.T., Zappulla D.C., Glynn E.F., Baumann P. A flexible template boundary element in the rna subunit of fission yeast telomerase. Garcia-Beccaria M., Martinez P., Mendez-Pertuz M., Martinez S., Blanco-Aparicio C., Canamero M., Mulero F., Ambrogio C., Flores J.M., Megias D., et al. Telomerase is a holoenzyme composed of the catalytic subunit, TERT (telomerase reverse transcriptase), and the RNA component, TERC (telomerase RNA component). In the cell lines with TERT promoter mutations, the methylation was shown to be allele-specific, and H3K27me3 and H3K9me3 histone marks of inactivation promote the methylation [146]. Gay-Bellile M., Veronese L., Combes P., Eymard-Pierre E., Kwiatkowski F., Dauplat M.M., Cayre A., Privat M., Abrial C., Bignon Y.J., et al. Rachakonda S., Srinivas N., Mahmoudpour S.H., Garcia-Casado Z., Requena C., Traves V., Soriano V., Cardelli M., Pjanova D., Molven A., et al. Allele-specific DNA methylation and its interplay with repressive histone marks at promoter-mutant tert genes. Telomere shortening, to an extent, in proliferating cells of self-renewal tissues, such as hematopoietic cells, cells of the skin, and cells from gastrointestinal epithelium, is mitigated by holoenzyme telomerase [5,12,95]. Mangino M., Richards J.B., Soranzo N., Zhai G., Aviv A., Valdes A.M., Samani N.J., Deloukas P., Spector T.D. Transcription factors such as SNAIL1, involved in the epithelial-to-mesenchymal transition, control telomere transcription, and integrity by negatively regulating TERRA [81]. The individuals signature of telomere length distribution. Telomeres are the ends of our chromosomes and function to protect them from damage. An integrative review of factors associated with telomere length and implications for biobehavioral research. The region surrounding the SNP exhibited the heterochromatin mark, H3K4me3, and the minor allele was shown to disrupt a putative binding sequence for Nuclear Factor Y (NF-Y) transcription factor, which is essential for TERC expression [185,205]. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Identification of atpases pontin and reptin as telomerase components essential for holoenzyme assembly. POT1 represses the ATM- and RAD3- related protein (ATR)-dependent signaling pathway and protects the telomere ends from fusion [50]. Marathon runners and triathletes that run 50 miles a week for 35 years have telomeres of individuals half their age. The test was developed in 2006 by Canadian researcher Peter Lansdorp, M.D., Ph.D. This is the beautiful solution that nature found to the problem of incomplete DNA replication at the ends of linear chromosomes. Inclusion in an NLM database does not imply endorsement of, or agreement with, Adler N., Pantell M.S., ODonovan A., Blackburn E., Cawthon R., Koster A., Opresko P., Newman A., Harris T.B., Epel E. Educational attainment and late life telomere length in the health, aging and body composition study. Ctc1-mediated c-strand fill-in is an essential step in telomere length maintenance. Kote-Jarai Z., Saunders E.J., Leongamornlert D.A., Tymrakiewicz M., Dadaev T., Jugurnauth-Little S., Ross-Adams H., Al Olama A.A., Benlloch S., Halim S., et al. You can lengthen telomeres by increasing telomerase activity. Telomeres, due to high guanine content, are targets of oxidative damage through the formation of 8-hydroxy-2-deoxyguanosine (8-oxodG), an important marker of oxidative stress, which causes accelerated shortening [214,215]. The werner syndrome helicase and exonuclease cooperate to resolve telomeric d loops in a manner regulated by trf1 and trf2. TERT promoter mutations contribute to tumorigenesis in a two-step mechanism. Some of the proteins associated with telomeres are also involved in the DDR mechanism [57]. Htert gene amplification and increased mrna expression in central nervous system embryonal tumors. Cancer Res. Aksenova A.Y., Mirkin S.M. Schematic representation of lagging and leading strand replication. Thus, the telomeres can be replenished. THOR methylation has been reported to have a diagnostic and prognostic role in pediatric brain tumors and prostate cancer [149,150]. The first OB fold binds to the hexamer repeat at the beginning of the strand while the second OB fold binds and protects the 3 G-overhang [48,49]. The human cst complex is a terminator of telomerase activity. NA, data not available. The G-tail can also fold into a four-stranded helical structure known as the G-quadruplex (Figure 1C) that involves stacking of G-quartets and intra-molecular folding by overcoming kinetic barriers, with each quartet formed by the association of four guanines into a cyclic Hoogsten hydrogen-bonding arrangement [19,20]. Role of telomeres and telomerase in cancer. Systematic correlation of environmental exposure and physiological and self-reported behaviour factors with leukocyte telomere length. Identification of seven loci affecting mean telomere length and their association with disease. Heidenreich B., Kumar R. Tert promoter mutations in telomere biology. Other somatic TERT promoter mutations that create identical binding sites for ETS/TCF transcription factors include that detected at 57 bp, originally discovered as the causal germline mutation in a melanoma pedigree, and at 124/125 bp and 138/139 bp as CC > TT tandem mutations that occur mainly in skin cancers [130,132,133,134]. Di Maro S., Zizza P., Salvati E., De Luca V., Capasso C., Fotticchia I., Pagano B., Marinelli L., Gilson E., Novellino E., et al. Pursell Z.F., Isoz I., Lundstrom E.B., Johansson E., Kunkel T.A. As a library, NLM provides access to scientific literature. THOR is hypermethylated in malignant tumors and hypomethylated in normal tissues and stem cells. Telomerase inhibitors such as small molecule inhibitors, antisense nucleotides, G-quadruplex stabilizers, TERT-dependent anticancer immunotherapy, and chemical inhibition of telomerase are the most commonly studied anti-cancer treatment strategies [251,252]. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Gu P., Chang S. Functional characterization of human ctc1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease coats plus. Yeast DNA polymerase epsilon participates in leading-strand DNA replication. and transmitted securely. A role for ctcf and cohesin in subtelomere chromatin organization, terra transcription, and telomere end protection. Investigation of leukocyte telomere length and genetic variants in chromosome 5p15.33 as prognostic markers in lung cancer. Pike A.M., Strong M.A., Ouyang J.P.T., Greider C.W. Telomere length is considered a biomarker of aging; shorter telomeres are associated with a decreased life expectancy and increased rates of age-related chronic diseases. Mutations in tert, the gene for telomerase reverse transcriptase, in aplastic anemia. While POT1 directly binds to single-stranded DNA, it indirectly interacts with the double-stranded DNA through association with TPP1 [46]. Prescott J., Kraft P., Chasman D.I., Savage S.A., Mirabello L., Berndt S.I., Weissfeld J.L., Han J., Hayes R.B., Chanock S.J., et al. 2. In 2010, telomere length was measured in skeletal muscle of 18 experienced middle-aged endurance runners versus 19 sedentary subjects . Venteicher A.S., Abreu E.B., Meng Z., McCann K.E., Terns R.M., Veenstra T.D., Terns M.P., Artandi S.E. CST complex is a heterotrimeric protein consisting of conserved telomere protection component 1 (CTC1), suppressor of cdc13 a (STN1), and telomeric pathway with STN1 (TEN1), which specifically localize to the single-stranded 3 overhang and protect the telomeres by mediating DNA replication and telomerase regulation, independent of shelterin complex.
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