Skip to main content
SpringerLink
Log in

Human Chromosome Telomeres

  • Chapter
  • First Online:
Human Genome Structure, Function and Clinical Considerations

Abstract

Telomeres are specialized sequences at the end of linear chromosomes. Its conserved structure and function among eukaryotic cells suggest important evolutionary functions. Telomere dynamics play major roles in chromosomal integrity, stability, cellular replication and aging, performing crucial genome protective functions. In the majority of somatic cells, telomeres shorten in each round of cell replication. Whereas short telomeres are a trigger for apoptosis, accelerated attrition is a hallmark of aging, present in senescent and tumoral cells. Compensation for erosion in germinal and progenitor cells is accomplished by the telomerase enzyme, composed of a catalytic (TERT) and a RNA template (TR) subunits. Telomerase activity is tightly controlled with reactivation central for tumoral transformation. Clinical evidence suggests that telomeres’ shortening that causally contributes to the establishment of specific progeria syndromes phenotypes are telomeropathies. In other cases, aging is accompanied by an abrupt telomere shortening in the context of chronic diseases, proposing telomeres length as an important biological pace marker for progression of various pathologies and aging. Because cancer cells reactivate TERT to compensate for telomeric loss, in the last decades, telomerase and the telomeres biology field have been subject to intense research in search for therapeutical targets for cancer. This chapter mainly focuses on basic telomere description and synthesis accomplished by the reverse transcriptase telomerase and its regulation. A final section addresses the understanding of telomeres in health and its contribution to cancer with therapeutic potentials for targeted inhibition.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    PARN: Poly(A)-Specific Ribonuclease.

  2. 2.

    RTEL: Regulator Of Telomere Elongation Helicase 1.

References

  1. Muller JH. The remaking of chromosomes. Collect Net. 1938;3:181–98.

    Google Scholar 

  2. McClintock B. The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc Natl Acad Sci U S A. 1939; https://doi.org/10.1073/pnas.25.8.405.

  3. Blackburn EH, Gall JG. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol. 1978; https://doi.org/10.1016/0022-2836(78)90294-2.

  4. Szostak JW, Blackburn EH. Cloning yeast telomeres on linear plasmid vectors. Cell. 1982;29:245–55.

    Article  CAS  PubMed  Google Scholar 

  5. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.

    Article  CAS  PubMed  Google Scholar 

  6. Watson J. Origin of concatemeric T7DNA. Nature. 1972; https://doi.org/10.1038/10.1038/newbio239197a0.

  7. Olovnikov AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973; https://doi.org/10.1016/0022-5193(73)90198-7.

  8. Hiyama K, et al. Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol. 1995;155:3711–5.

    CAS  PubMed  Google Scholar 

  9. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990; https://doi.org/10.1038/345458a0.

  10. Hastie ND, et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature. 1990;346:866–8.

    Article  CAS  PubMed  Google Scholar 

  11. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in tetrahymena extracts. Cell. 1985;43:405–13.

    Article  CAS  PubMed  Google Scholar 

  12. Lundblad V, Szostak JW. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell. 1989; https://doi.org/10.1016/0092-8674(89)90132-3.

  13. Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012;13:693–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Herbert BS, et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci U S A. 1999; https://doi.org/10.1073/pnas.96.25.14276.

  15. Blackburn EH, Epel ES, Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science (80-). 2015;350:1193–8.

    Article  CAS  Google Scholar 

  16. Meyne J, Ratliff RL, Moyzis RK. Conservation of the human telomere sequence (TTAGGG)(n) among vertebrates. Proc Natl Acad Sci U S A. 1989; https://doi.org/10.1073/pnas.86.18.7049.

  17. Blackburn EH, Collins K. Telomerase: an RNP enzyme synthesizes DNA. Cold Spring Harb Perspect Biol. 2011; https://doi.org/10.1101/cshperspect.a003558.

  18. Griffith JD, et al. Mammalian telomeres end in a large duplex loop. Cell. 1999; https://doi.org/10.1016/S0092-8674(00)80760-6.

  19. Erdel F, et al. Telomere recognition and assembly mechanism of mammalian shelterin. Cell Rep. 2017; https://doi.org/10.1016/j.celrep.2016.12.005.

  20. Shay JW, Wright WE. Telomeres and telomerase in normal and cancer stem cells. FEBS Lett. 2010; https://doi.org/10.1016/j.febslet.2010.05.026.

  21. De Lange T. T-loops and the origin of telomeres. Nat Rev Mol Cell Biol. 2004; https://doi.org/10.1038/nrm1359.

  22. Palm W, De Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet. 2008; https://doi.org/10.1146/annurev.genet.41.110306.130350.

  23. Doksani Y, Wu JY, De Lange T, Zhuang X. XSuper-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell. 2013; https://doi.org/10.1016/j.cell.2013.09.048.

  24. De Lange T. Shelterin-mediated telomere protection. Annu Rev Genet. 2018; https://doi.org/10.1146/annurev-genet-032918-021921.

  25. Van Ly D, et al. Telomere loop dynamics in chromosome end protection. Mol Cell. 2018; https://doi.org/10.1016/j.molcel.2018.06.025.

  26. Denchi EL, De Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature. 2007; https://doi.org/10.1038/nature06065.

  27. Xu Y. Chemistry in human telomere biology: structure, function and targeting of telomere DNA/RNA. Chem Soc Rev. 2011; https://doi.org/10.1039/c0cs00134a.

  28. Collins K, Mitchell JR. Telomerase in the human organism. Oncogene. 2002; https://doi.org/10.1038/sj/onc/1205083.

  29. Tan J, Lan L. The DNA secondary structures at telomeres and genome instability. Cell Biosci. 2020; https://doi.org/10.1186/s13578-020-00409-z.

  30. Zaug AJ, Podell ER, Cech TR. Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proc Natl Acad Sci U S A. 2005; https://doi.org/10.1073/pnas.0504744102.

  31. Bhattacharjee A, Wang Y, Diao J, Price CM. Dynamic DNA binding, junction recognition and G4 melting activity underlie the telomeric and genome-wide roles of human CST. Nucleic Acids Res. 2017; https://doi.org/10.1093/nar/gkx878.

  32. Martínez P, Blasco MA. Replicating through telomeres: a means to an end. Trends Biochem Sci. 2015; https://doi.org/10.1016/j.tibs.2015.06.003.

  33. Eisenberg DTA. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Am J Hum Biol. 2011; https://doi.org/10.1002/ajhb.21127.

  34. Bryan TM, Cech TR. Telomerase and the maintenance of chromosome ends. Curr Opin Cell Biol. 1999; https://doi.org/10.1016/S0955-0674(99)80043-X.

  35. Autexier C, Lue NF. The structure and function of telomerase reverse transcriptase. Annu Rev Biochem. 2006; https://doi.org/10.1146/annurev.biochem.75.103004.142412.

  36. Nassour J, et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature. 2019; https://doi.org/10.1038/s41586-019-0885-0.

  37. Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019; https://doi.org/10.1038/s41576-019-0099-1.

  38. Viviescas MA, Cano MIN, Segatto M. Chaperones and their role in telomerase ribonucleoprotein biogenesis and telomere maintenance. Curr Proteomics. 2018; https://doi.org/10.2174/1570164615666180713103133.

  39. Rubtsova M, Dontsova O. Human telomerase RNA: telomerase component or more? Biomol Ther. 2020; https://doi.org/10.3390/biom10060873.

  40. Nguyen KTTT, Wong JMY. Telomerase biogenesis and activities from the perspective of its direct interacting partners. Cancers. 2020; https://doi.org/10.3390/cancers12061679.

  41. Musgrove C, Jansson LI, Stone MD. New perspectives on telomerase RNA structure and function. Wiley Interdisciplinary Reviews: RNA. 2018; https://doi.org/10.1002/wrna.1456.

  42. Roake CM, Artandi SE. Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol. 2020; https://doi.org/10.1038/s41580-020-0234-z.

  43. Wyatt HDM, West SC, Beattie TL. InTERTpreting telomerase structure and function. Nucleic Acids Res. 2010; https://doi.org/10.1093/nar/gkq370.

  44. Hukezalie KR, Wong JMY. Structure-function relationship and biogenesis regulation of the human telomerase holoenzyme. FEBS J. 2013; https://doi.org/10.1111/febs.12272.

  45. Patrick EM, Slivka JD, Payne B, Comstock MJ, Schmidt JC. Observation of processive telomerase catalysis using high-resolution optical tweezers. Nat Chem Biol. 2020; https://doi.org/10.1038/s41589-020-0478-0.

  46. Thompson CAH, Wong JMY. Non-canonical functions of telomerase reverse transcriptase: emerging roles and biological relevance. Curr Top Med Chem. 2020; https://doi.org/10.2174/1568026620666200131125110.

  47. Feng J, et al. The RNA component of human telomerase. Science (80-). 1995; https://doi.org/10.1126/science.7544491.

  48. Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature. 1999;402:551–5.

    Article  CAS  PubMed  Google Scholar 

  49. Rubtsova M, et al. Protein encoded in human telomerase RNA is involved in cell protective pathways. Nucleic Acids Res. 2018; https://doi.org/10.1093/nar/gky705.

  50. Calado RT, et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS One. 2009; https://doi.org/10.1371/journal.pone.0007926.

  51. Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009; https://doi.org/10.1056/nejmra0903373.

  52. Wu P, Takai H, De Lange T. Telomeric 3′ overhangs derive from resection by Exo1 and apollo and fill-in by POT1b-associated CST. Cell. 2012; https://doi.org/10.1016/j.cell.2012.05.026.

  53. Chow TT, Zhao Y, Mak SS, Shay JW, Wright WE. Early and late steps in telomere overhang processing in normal human cells: the position of the final RNA primer drives telomere shortening. Genes Dev. 2012; https://doi.org/10.1101/gad.187211.112.

  54. Londoño-Vallejo JA, Der-Sarkissian H, Cazes L, Bacchetti S, Reddel RR. Alternative lengthening of telomeres is characterized by high rates of telomeric exchange. Cancer Res. 2004; https://doi.org/10.1158/0008-5472.CAN-03-4035.

  55. Lee M, et al. Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes. Nucleic Acids Res. 2014; https://doi.org/10.1093/nar/gkt1117.

  56. Episkopou H, et al. Alternative lengthening of telomeres is characterized by reduced compaction of telomeric chromatin. Nucleic Acids Res. 2014; https://doi.org/10.1093/nar/gku114.

  57. Udroiu I, Sgura A. Alternative lengthening of telomeres and chromatin status. Genes. 2020; https://doi.org/10.3390/genes11010045.

  58. Conomos D, et al. Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells. J Cell Biol. 2012;199:893–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xu M, et al. Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway. Sci Adv. 2019; https://doi.org/10.1126/sciadv.aax6366.

  60. Yeager TR, et al. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res. 1999;

    Google Scholar 

  61. Fasching CL, Neumann AA, Muntoni A, Yeager TR, Reddel RR. DNA damage induces alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA. Cancer Res. 2007; https://doi.org/10.1158/0008-5472.CAN-07-1556.

  62. Chung I, Leonhardt H, Rippe K. De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation. J Cell Sci. 2011; https://doi.org/10.1242/jcs.084681.

  63. Hoang SM, O’Sullivan RJ. Alternative lengthening of telomeres: building bridges to connect chromosome ends. Trends Cancer. 2020; https://doi.org/10.1016/j.trecan.2019.12.009.

  64. De Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005; https://doi.org/10.1101/gad.1346005.

  65. Lim CJ, Zaug AJ, Kim HJ, Cech TR. Reconstitution of human shelterin complexes reveals unexpected stoichiometry and dual pathways to enhance telomerase processivity. Nat Commun. 2017; https://doi.org/10.1038/s41467-017-01313-w.

  66. Hanaoka S, Nagadoi A, Nishimura Y. Comparison between TRF2 and TRF1 of their telomeric DNA-bound structures and DNA-binding activities. Protein Sci. 2009; https://doi.org/10.1110/ps.04983705.

  67. Rai R, Chen Y, Lei M, Chang S. TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun. 2016; https://doi.org/10.1038/ncomms10881.

  68. Diotti R, Loayza D. Shelterin complex and associated factors at human telomeres. Nucleus. 2011; https://doi.org/10.4161/nucl.2.2.15135.

  69. Schmutz I, De Lange T. Shelterin. Curr Biol. 2016; https://doi.org/10.1016/j.cub.2016.01.056.

  70. De Lange T. How shelterin solves the telomere end-protection problem. Cold Spring Harb Symp Quant Biol. 2010; https://doi.org/10.1101/sqb.2010.75.017.

  71. Wang F, et al. The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature. 2007; https://doi.org/10.1038/nature05454.

  72. Kibe T, Zimmermann M, de Lange T. TPP1 blocks an ATR-mediated resection mechanism at telomeres. Mol Cell. 2016; https://doi.org/10.1016/j.molcel.2015.12.016.

  73. Lei M, Podell ER, Cech TR. Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat Struct Mol Biol. 2004; https://doi.org/10.1038/nsmb867.

  74. Chen Y. The structural biology of the shelterin complex. Biol Chem. 2019; https://doi.org/10.1515/hsz-2018-0368.

  75. Arango HG. Bioestatística: Teórica e computacional. 2009.

    Google Scholar 

  76. Janovič T, Stojaspal M, Veverka P, Horáková D, Hofr C. Human telomere repeat binding factor TRF1 replaces TRF2 bound to shelterin core hub TIN2 when TPP1 is absent. J Mol Biol. 2019; https://doi.org/10.1016/j.jmb.2019.05.038.

  77. Wellinger RJ. The CST complex and telomere maintenance: the exception becomes the rule. Mol Cell. 2009; https://doi.org/10.1016/j.molcel.2009.10.001.

  78. Miyake Y, et al. RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol Cell. 2009; https://doi.org/10.1016/j.molcel.2009.08.009.

  79. Price CM, et al. Evolution of CST function in telomere maintenance. Cell Cycle. 2010; https://doi.org/10.4161/cc.9.16.12547.

  80. Rice C, Skordalakes E. Structure and function of the telomeric CST complex. Comput Struct Biotechnol J. 2016; https://doi.org/10.1016/j.csbj.2016.04.002.

  81. Wold MS. Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem. 1997; https://doi.org/10.1146/annurev.biochem.66.1.61.

  82. Chen LY, Redon S, Lingner J. The human CST complex is a terminator of telomerase activity. Nature. 2012; https://doi.org/10.1038/nature11269.

  83. Bryan C, Rice C, Harkisheimer M, Schultz DC, Skordalakes E. Structure of the human telomeric Stn1-Ten1 capping complex. PLoS One. 2013; https://doi.org/10.1371/journal.pone.0066756.

  84. Chen LY, Majerská J, Lingner J. Molecular basis of telomere syndrome caused by CTC1 mutations. Genes Dev. 2013; https://doi.org/10.1101/gad.222893.113.

  85. Simon AJ, et al. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016; https://doi.org/10.1084/jem.20151618.

  86. Amir M, et al. Structural features of nucleoprotein CST/shelterin complex involved in the telomere maintenance and its association with disease mutations. Cell. 2020; https://doi.org/10.3390/cells9020359.

  87. Wang F, Stewart J, Price CM. Human CST abundance determines recovery from diverse forms of DNA damage and replication stress. Cell Cycle. 2014; https://doi.org/10.4161/15384101.2014.964100.

  88. Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J. Telomeric repeat-containing RNA and RNA surveillance factors at mammalian chromosome ends. Science (80-). 2007; https://doi.org/10.1126/science.1147182.

  89. Luke B, et al. The Rat1p 5′ to 3′ exonuclease degrades telomeric repeat-containing RNA and promotes telomere elongation in Saccharomyces cerevisiae. Mol Cell. 2008; https://doi.org/10.1016/j.molcel.2008.10.019.

  90. Schoeftner S, Blasco MA. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol. 2008; https://doi.org/10.1038/ncb1685.

  91. Bah A, Wischnewski H, Shchepachev V, Azzalin CM. The telomeric transcriptome of Schizosaccharomyces pombe. Nucleic Acids Res. 2012; https://doi.org/10.1093/nar/gkr1153.

  92. Cusanelli E, Romero CAP, Chartrand P. Telomeric noncoding RNA TERRA is induced by telomere shortening to nucleate telomerase molecules at short telomeres. Mol Cell. 2013; https://doi.org/10.1016/j.molcel.2013.08.029.

  93. Bettin N, Oss Pegorar C, Cusanelli E. The emerging roles of TERRA in telomere maintenance and genome stability. Cell. 2019; https://doi.org/10.3390/cells8030246.

  94. Azzalin CM, Lingner J. Telomere functions grounding on TERRA firma. Trends Cell Biol. 2015; https://doi.org/10.1016/j.tcb.2014.08.007.

  95. Kwapisz M, Morillon A. Subtelomeric transcription and its regulation. J Mol Biol. 2020; https://doi.org/10.1016/j.jmb.2020.01.026.

  96. Nergadze SG, et al. CpG-island promoters drive transcription of human telomeres. RNA. 2009; https://doi.org/10.1261/rna.1748309.

  97. Farnung BO, Giulotto E, Azzalin CM. Promoting transcription of chromosome ends. Transcription. 2010; https://doi.org/10.4161/trns.1.3.13191.

  98. Pfeiffer V, Lingner J. TERRA promotes telomere shortening through exonuclease 1-mediated resection of chromosome ends. PLoS Genet. 2012; https://doi.org/10.1371/journal.pgen.1002747.

  99. Porro A, Feuerhahn S, Reichenbach P, Lingner J. Molecular dissection of telomeric repeat-containing RNA biogenesis unveils the presence of distinct and multiple regulatory pathways. Mol Cell Biol. 2010; https://doi.org/10.1128/mcb.00460-10.

  100. Feuerhahn S, Iglesias N, Panza A, Porro A, Lingner J. TERRA biogenesis, turnover and implications for function. FEBS Lett. 2010; https://doi.org/10.1016/j.febslet.2010.07.032.

  101. Schoeftner S, Blasco MA. A higher order of telomere regulation: telomere heterochromatin and telomeric RNAs. EMBO J. 2009; https://doi.org/10.1038/emboj.2009.197.

  102. Porro A, et al. Functional characterization of the TERRA transcriptome at damaged telomeres. Nat Commun. 2014; https://doi.org/10.1038/ncomms6379.

  103. Feretzaki M, Nunes PR, Lingner J. Expression and differential regulation of human TERRA at several chromosome ends. RNA. 2019; https://doi.org/10.1261/rna.072322.119.

  104. Redon S, Reichenbach P, Lingner J. The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res. 2010; https://doi.org/10.1093/nar/gkq296.

  105. Yehezkel S, et al. Characterization and rescue of telomeric abnormalities in ICF syndrome type I fibroblasts. Front Oncol. 2013; https://doi.org/10.3389/fonc.2013.00035.

  106. Sagie S, et al. Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids. Nat Commun. 2017; https://doi.org/10.1038/ncomms14015.

  107. De Silanes IL, et al. Identification of TERRA locus unveils a telomere protection role through association to nearly all chromosomes. Nat Commun. 2014; https://doi.org/10.1038/ncomms5723.

  108. Cusanelli E, Chartrand P. Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity. Front Genet. 2015; https://doi.org/10.3389/fgene.2015.00143.

  109. Montero JJ, López De Silanes I, Granã O, Blasco MA. Telomeric RNAs are essential to maintain telomeres. Nat Commun. 2016; https://doi.org/10.1038/ncomms12534.

  110. Arora R, Brun CMC, Azzalin CM. TERRA: long noncoding RNA at eukaryotic telomeres. Prog Mol Subcell Biol. 2011;51

    Google Scholar 

  111. Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman PM. TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell. 2009; https://doi.org/10.1016/j.molcel.2009.06.025.

  112. Redon S, Zemp I, Lingner J. A three-state model for the regulation of telomerase by TERRA and hnRNPA1. Nucleic Acids Res. 2013; https://doi.org/10.1093/nar/gkt695.

  113. Postepska-Igielska A, et al. The chromatin remodelling complex NoRC safeguards genome stability by heterochromatin formation at telomeres and centromeres. EMBO Rep. 2013; https://doi.org/10.1038/embor.2013.87.

  114. Montero JJ, et al. TERRA recruitment of polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin. Nat Commun. 2018; https://doi.org/10.1038/s41467-018-03916-3.

  115. Chu HP, et al. TERRA RNA antagonizes ATRX and protects telomeres. Cell. 2017; https://doi.org/10.1016/j.cell.2017.06.017.

  116. Biffi G, Tannahill D, Balasubramanian S. An intramolecular G-quadruplex structure is required for binding of telomeric repeat-containing RNA to the telomeric protein TRF2. J Am Chem Soc. 2012; https://doi.org/10.1021/ja305734x.

  117. Aguado J, d’Adda di Fagagna F, Wolvetang E. Telomere transcription in ageing. Ageing Res Rev. 2020; https://doi.org/10.1016/j.arr.2020.101115.

  118. Avogaro L, et al. Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells. RNA Biol. 2018; https://doi.org/10.1080/15476286.2018.1456300.

  119. Collie GW, Haider SM, Neidle S, Parkinson GN. A crystallographic and modelling study of a human telomeric RNA (TERRA) quadruplex. Nucleic Acids Res. 2010; https://doi.org/10.1093/nar/gkq259.

  120. Blackburn EH, Greider CW, Szostak JW. Telomeres and telomerase: the path from maize. Tetrahymena and yeast to human cancer and aging. Nat Med. 2006; https://doi.org/10.1038/nm1006-1133.

  121. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Martínez P, Blasco MA. Heart-breaking telomeres. Circ Res. 2018;123:787–802.

    Article  PubMed  CAS  Google Scholar 

  123. Takubo K, et al. Telomere shortening with aging in human liver. J Gerontol - Ser A Biol Sci Med Sci. 2000;55:B533–6.

    Article  CAS  Google Scholar 

  124. Song Z, et al. Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood. Aging Cell. 2010;9:607–15.

    Article  CAS  PubMed  Google Scholar 

  125. Jiang H, et al. Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc Natl Acad Sci U S A. 2008;105:11299–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Demissie S, et al. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell. 2006;5:325–30.

    Article  CAS  PubMed  Google Scholar 

  127. Diez Roux AV, et al. Race/ethnicity and telomere length in the multi-ethnic study of atherosclerosis. Aging Cell. 2009;8:251–7.

    Article  CAS  PubMed  Google Scholar 

  128. Hunt SC, et al. Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study. Aging Cell. 2008;7:451–8.

    Article  CAS  PubMed  Google Scholar 

  129. Cherkas LF, et al. The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med. 2008;168:154–8.

    Article  PubMed  Google Scholar 

  130. Lapham K, et al. Automated assay of telomere length measurement and informatics for 100,000 subjects in the genetic epidemiology research on adult health and aging (GERA) cohort. Genetics. 2015;200:1061–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Andrew T, et al. Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. Am J Hum Genet. 2006;78:480–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Levy D, et al. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci U S A. 2010;107:9293–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Vasa-Nicotera M, et al. Mapping of a major locus that determines telomere length in humans. Am J Hum Genet. 2005;76:147–51.

    Article  CAS  PubMed  Google Scholar 

  134. Mangino M, et al. A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans. Hum Mol Genet. 2008;17:2518–23.

    Article  CAS  PubMed  Google Scholar 

  135. Codd V, et al. Common variants near TERC are associated with mean telomere length. Nat Genet. 2010;42:197–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Takubo K, et al. Telomere lengths are characteristic in each human individual. Exp Gerontol. 2002;37:523–31.

    Article  CAS  PubMed  Google Scholar 

  137. Canela A, Vera E, Klatt P, Blasco MA. High-throughput telomere length quantification by FISH and its application to human population studies. Proc Natl Acad Sci U S A. 2007;104:5300–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ehrlenbach S, et al. Influences on the reduction of relative telomere length over 10 years in the population-based bruneck study: Introduction of a well-controlled high-throughput assay. Int J Epidemiol. 2009;38:1725–34.

    Article  PubMed  Google Scholar 

  139. Valdes AM, et al. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005;366:662–4.

    Article  CAS  PubMed  Google Scholar 

  140. O’Donnell CJ, et al. Leukocyte telomere length and carotid artery intimai medial thickness R the framingham heart study. Arterioscler Thromb Vasc Biol. 2008;28:1165–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Pavanello S, et al. Shortened telomeres in individuals with abuse in alcohol consumption. Int J Cancer. 2011;129:983–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Strandberg TE, et al. Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki Businessmen Study. 2012. https://doi.org/10.1007/s10654-012-9728-0.

  143. Martens DS, et al. Association of parental socioeconomic status and newborn telomere length. JAMA Netw Open. 2020;3:e204057.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Kemp BR, Ferraro KF. Are biological consequences of childhood exposures detectable in telomere length decades later? J Gerontol Ser A. 2021; https://doi.org/10.1093/gerona/glaa019.

  145. Tucker LA. Physical activity and telomere length in U.S. men and women: an NHANES investigation. Prev Med (Baltim). 2017;100:145–51.

    Article  Google Scholar 

  146. Du M, et al. Physical activity, sedentary behavior, and leukocyte telomere length in women. Am J Epidemiol. 2012;175:414–22.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Arem H, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med. 2015;175:959–67.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Starr JM, et al. Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey. Mech Ageing Dev. 2008;129:745–51.

    Article  CAS  PubMed  Google Scholar 

  149. Von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002; https://doi.org/10.1016/S0968-0004(02)02110-2.

  150. Ma D, Zhu W, Hu S, Yu X, Yang Y. Association between oxidative stress and telomere length in type 1 and type 2 diabetic patients. J Endocrinol Investig. 2013;36:1032–7.

    CAS  Google Scholar 

  151. Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA. Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care. 2006;29:283–9.

    Article  CAS  PubMed  Google Scholar 

  152. O’Donovan A, et al. Cumulative inflammatory load is associated with short leukocyte telomere length in the health, aging and body composition study. PLoS One. 2011;6

    Google Scholar 

  153. Al-Attas OS, et al. Adiposity and insulin resistance correlate with telomere length in middle-aged Arabs: the influence of circulating adiponectin. Eur J Endocrinol. 2010;163:601–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mawanda F, Wallace R. Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol Rev. 2013;35:161–80.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Von Zglinicki T, Pilger R, Sitte N. Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med. 2000; https://doi.org/10.1016/S0891-5849(99)00207-5.

  156. Townsley DM, et al. Danazol treatment for telomere diseases. N Engl J Med. 2016;374:1922–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Leteurtre F, et al. Accelerated telomere shortening and telomerase activation in Fanconi’s anaemia. Br J Haematol. 1999; https://doi.org/10.1046/j.1365-2141.1999.01445.x.

  158. Zinsser F. Atrophia cutis reticularis cum pigmentatione, dystrophia unguium et leukoplakia oris. Ikonogr Dermatol (Hyoto). 1910;5:219–23.

    Google Scholar 

  159. Costello MJ, Buncke CM. Dyskeratosis congenita. A M A Arch Dermatology. 1956; https://doi.org/10.1001/archderm.1956.01550020023004.

  160. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the national cancer institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018; https://doi.org/10.3324/haematol.2017.178111.

  161. Armanios M, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A. 2005;102:15960–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Vulliamy TJ, et al. Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood. 2006;107:2680–5.

    Article  CAS  PubMed  Google Scholar 

  163. Aalfs CM, van den Berg H, Barth PG, Hennekam RCM. The Hoyeraal-Hreidarsson syndrome: the fourth case of a separate entity with prenatal growth retardation, progressive pancytopenia and cerebellar hypoplasia. Eur J Pediatr. 1995; https://doi.org/10.1007/BF01957367.

  164. Revesz T, Fletcher S, Al-Gazali LI, DeBuse P. Bilateral retinopathy, aplastic anaemia, and central nervous system abnormalities: a new syndrome? J Med Genet. 1992; https://doi.org/10.1136/jmg.29.9.673.

  165. Kajtar P, Mehes K. Bilateral Coats retinopathy associated with aplastic anaemia and mild dyskeratotic signs. Am J Med Genet. 1994; https://doi.org/10.1002/ajmg.1320490404.

  166. Ehrlich P. Über einen Fall von Anämie mit Bemerkungen über regenerative Veränderungen des Knochenmarks, Charité-Ann. 1888.

    Google Scholar 

  167. Arias-Salgado EG, et al. Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes. Orphanet J Rare Dis. 2019;14:82.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Savage SA, et al. Genetic variation in telomeric repeat binding factors 1 and 2 in aplastic anemia. Exp Hematol. 2006; https://doi.org/10.1016/j.exphem.2006.02.008.

  169. Marsh JW, et al. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms. Blood Adv. 2018; https://doi.org/10.1182/bloodadvances.2017008110.

  170. Fernández Pérez ER, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis a population-based study. Chest. 2010;137:129–37.

    Article  PubMed  Google Scholar 

  171. Hodgson U, Laitinen T, Tukiainen P. Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Thorax. 2002;57:338–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kim HJ, Perlman D, Tomic R. Natural history of idiopathic pulmonary fibrosis. Respir Med. 2015; https://doi.org/10.1016/j.rmed.2015.02.002.

  173. Armanios MY, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356:1317–26.

    Article  CAS  PubMed  Google Scholar 

  174. Tsakiri KD, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007;104:7552–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Stuart BD, et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet. 2015; https://doi.org/10.1038/ng.3278.

  176. Fingerlin TE, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet. 2013; https://doi.org/10.1038/ng.2609.

  177. Alder JK, et al. Exome sequencing identifi es mutant TINF2 in a family with pulmonary fibrosis. Chest. 2015;147:1361–8.

    Article  PubMed  Google Scholar 

  178. Alder JK, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008; https://doi.org/10.1073/pnas.0804280105.

  179. Parry EM, Alder JK, Qi X, Chen JJL, Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood. 2011; https://doi.org/10.1182/blood-2010-11-322149.

  180. De Sandre-Giovannoli A, et al. Lamin A truncation in Hutchinson-Gilford progeria. Science (80-). 2003;300:2055.

    Article  Google Scholar 

  181. Eriksson M, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293–8.

    Article  CAS  PubMed  Google Scholar 

  182. Benson EK, Lee SW, Aaronson SA. Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J Cell Sci. 2010; https://doi.org/10.1242/jcs.067306.

  183. Decker ML, Chavez E, Vulto I, Lansdorp PM. Telomere length in Hutchinson-Gilford Progeria Syndrome. Mech Ageing Dev. 2009; https://doi.org/10.1016/j.mad.2009.03.001.

  184. Crabbe L, Cesare AJ, Kasuboski JM, Fitzpatrick JAJ, Karlseder J. Human telomeres are tethered to the nuclear envelope during postmitotic nuclear assembly. Cell Rep. 2012; https://doi.org/10.1016/j.celrep.2012.11.019.

  185. Chojnowski A, et al. Progerin reduces LAP2α-telomere association in hutchinson-gilford progeria. elife. 2015; https://doi.org/10.7554/eLife.07759.

  186. Wood AM, et al. TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends. Nat Commun. 2014; https://doi.org/10.1038/ncomms6467.

  187. Wood LD, et al. Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression. Oncogene. 2001; https://doi.org/10.1038/sj.onc.1204072.

  188. Crabbe L, Verdun RE, Haggblom CI, Karlseder J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science (80-). 2004; https://doi.org/10.1126/science.1103619.

  189. Collopy LC, et al. Triallelic and epigenetic-like inheritance in human disorders of telomerase. Blood. 2015; https://doi.org/10.1182/blood-2015-03-633388.

  190. Brouilette S, Singh RK, Thompson JR, Goodall AH, Samani NJ. White cell telomere length and risk of premature myocardial infarction. Arterioscler Thromb Vasc Biol. 2003; https://doi.org/10.1161/01.ATV.0000067426.96344.32.

  191. Codd V, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013; https://doi.org/10.1038/ng.2528.

  192. Révész D, Milaneschi Y, Verhoeven JE, Penninx BWJH. Telomere length as a marker of cellular aging is associated with prevalence and progression of metabolic syndrome. J Clin Endocrinol Metab. 2014; https://doi.org/10.1210/jc.2014-1851.

  193. Révész D, et al. Associations between cellular aging markers and metabolic syndrome: findings from the cardia study. J Clin Endocrinol Metab. 2018; https://doi.org/10.1210/jc.2017-01625.

  194. Sanders JL, et al. Leukocyte telomere length is associated with noninvasively measured age-related disease: the cardiovascular health study. J Gerontol Ser A Biol Sci Med Sci. 2012;67(A):409–16.

    Article  Google Scholar 

  195. Friis-Ottessen M, et al. Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis. BMC Gastroenterol. 2014; https://doi.org/10.1186/1471-230X-14-8.

  196. Grun LK, et al. TRF1 as a major contributor for telomeres’ shortening in the context of obesity. Free Radic Biol Med. 2018;129

    Google Scholar 

  197. Laimer M, et al. Telomere length increase after weight loss induced by bariatric surgery: results from a 10 year prospective study. Int J Obes. 2016; https://doi.org/10.1038/ijo.2015.238.

  198. Formichi C, et al. Weight loss associated with bariatric surgery does not restore short telomere length of severe obese patients after 1 year. Obes Surg. 2014;24:2089–93.

    Article  PubMed  Google Scholar 

  199. Bonfigli AR, et al. Leukocyte telomere length and mortality risk in patients with type 2 diabetes. Oncotarget. 2016; https://doi.org/10.18632/oncotarget.10615.

  200. Aulinas A, et al. Dyslipidemia and chronic inflammation markers are correlated with Telomere Length shortening in Cushing’s syndrome. PLoS One. 2015; https://doi.org/10.1371/journal.pone.0120185.

  201. Strazhesko I, et al. Association of insulin resistance, arterial stiffness and telomere length in adults free of cardiovascular diseases. PLoS One. 2015; https://doi.org/10.1371/journal.pone.0136676.

  202. Albrecht E, et al. Telomere length in circulating leukocytes is associated with lung function and disease. Eur Respir J. 2014;43:983–92.

    Article  PubMed  Google Scholar 

  203. Córdoba-Lanús E, et al. Telomere shortening and accelerated aging in COPD: findings from the BODE cohort. Respir Res. 2017; https://doi.org/10.1186/s12931-017-0547-4.

  204. Kyoh S, et al. Are leukocytes in asthmatic patients aging faster? A study of telomere length and disease severity. J Allergy Clin Immunol. 2013;132

    Google Scholar 

  205. Belsky DW, et al. Is chronic asthma associated with shorter leukocyte telomere length at midlife? Am J Respir Crit Care Med. 2014;190:384–91.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Scarabino D, et al. Leukocyte telomere shortening in Huntington’s disease. J Neurol Sci. 2019; https://doi.org/10.1016/j.jns.2018.10.024.

  207. Jing ZG, et al. A percentage analysis of the telomere length in Parkinson’s disease patients. J Gerontol Ser A Biol Sci Med Sci. 2008;63:467–73.

    Article  Google Scholar 

  208. Silva PNO, et al. Promoter methylation analysis of SIRT3, SMARCA5, HTERT and CDH1 genes in aging and Alzheimer’s disease. J Alzheimers Dis. 2008;13:173–6.

    Article  CAS  PubMed  Google Scholar 

  209. Zhan Y, et al. Telomere length shortening and Alzheimer disease-A mendelian randomization study. JAMA Neurol. 2015; https://doi.org/10.1001/jamaneurol.2015.1513.

  210. Barbé-Tuana FM, et al. Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease. Rev Bras Psiquiatr. 2016;38:281–6.

    Article  PubMed  PubMed Central  Google Scholar 

  211. Vasconcelos-Moreno MPMP, et al. Telomere length, oxidative stress, inflammation and BDNF levels in siblings of patients with bipolar disorder: implications for accelerated cellular aging. Int J Neuropsychopharmacol. 2017;20:445–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Czepielewski LSLS, et al. Telomere length and CCL11 levels are associated with gray matter volume and episodic memory performance in schizophrenia: evidence of pathological accelerated aging. Schizophr Bull. 2017;44:1–10.

    Google Scholar 

  213. Czepielewski LSLS, et al. Telomere length in subjects with schizophrenia, their unaffected siblings and healthy controls: evidence of accelerated aging. Schizophr Res. 2016;174:39–42.

    Article  PubMed  Google Scholar 

  214. Buxton JL, et al. Childhood obesity is associated with shorter leukocyte telomere length. J Clin Endocrinol Metab. 2011; https://doi.org/10.1210/jc.2010-2924.

  215. Li Z, He Y, Wang D, Tang J, Chen X. Association between childhood trauma and accelerated telomere erosion in adulthood: a meta-analytic study. J Psychiatr Res. 2017; https://doi.org/10.1016/j.jpsychires.2017.06.002.

  216. Mayer SE, et al. Cumulative lifetime stress exposure and leukocyte telomere length attrition: the unique role of stressor duration and exposure timing. Psychoneuroendocrinology. 2019; https://doi.org/10.1016/j.psyneuen.2019.03.002.

  217. Clemente DBP, et al. Prenatal and childhood traffic-related air pollution exposure and telomere length in european children: The HELIX project. Environ Health Perspect. 2019; https://doi.org/10.1289/EHP4148.

  218. Chiba K, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science (80-). 2017; https://doi.org/10.1126/science.aao0535.

  219. Kim NW, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–5.

    Article  CAS  PubMed  Google Scholar 

  220. Barthel FP, et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat Genet. 2017; https://doi.org/10.1038/ng.3781.

  221. Nguyen THD, et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature. 2018; https://doi.org/10.1038/s41586-018-0062-x.

  222. Vonderheide RH. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene. 2002; https://doi.org/10.1038/sj/onc/1205074.

  223. Lilleby W, et al. Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer. Cancer Immunol Immunother. 2017; https://doi.org/10.1007/s00262-017-1994-y.

  224. Middleton G, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 2014; https://doi.org/10.1016/S1470-2045(14)70236-0.

  225. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018; https://doi.org/10.3389/fonc.2018.00086.

  226. Nemunaitis J, et al. A phase i study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010; https://doi.org/10.1038/mt.2009.262.

  227. Mender I, Gryaznov S, Dikmen ZG, Wright WE, Shay JW. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer Discov. 2015; https://doi.org/10.1158/2159-8290.CD-14-0609.

  228. Chiappori AA, et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol. 2015; https://doi.org/10.1093/annonc/mdu550.

  229. Baerlocher GM, Burington B, Snyder DS. Telomerase inhibitor imetelstat in essential thrombocythemia and myelofibrosis. N Engl J Med. 2015;373:2579–81.

    Article  CAS  Google Scholar 

  230. Sinclair D, Fillman SG, Webster MJ, Weickert CS. Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness. Sci Rep. 2013;3:3539.

    Article  PubMed  PubMed Central  Google Scholar 

  231. Bryan C, et al. Structural basis of telomerase inhibition by the highly specific BIBR1532. Structure. 2015; https://doi.org/10.1016/j.str.2015.08.006.

  232. Liu C, Zhou H, Sheng XB, Liu XH, Chen FH. Design, synthesis and SARs of novel telomerase inhibitors based on BIBR1532. Bioorg Chem. 2020; https://doi.org/10.1016/j.bioorg.2020.104077.

  233. Bryce LA, Morrison N, Hoare SF, Muir S, Keith WN. Mapping of the gene for the human telomerase reverse transcriptase, hTERT, to chromosome 5p15.33 by fluorescence in situ hybridization. Neoplasia. 2000; https://doi.org/10.1038/sj.neo.7900092.

  234. Ramlee MK, Wang J, Toh WX, Li S. Transcription regulation of the human telomerase reverse transcriptase (hTERT) gene. Genes. 2016; https://doi.org/10.3390/genes7080050.

  235. Mancini A, et al. Disruption of the β1L isoform of GABP reverses glioblastoma replicative immortality in a TERT promoter mutation-dependent manner. Cancer Cell. 2018; https://doi.org/10.1016/j.ccell.2018.08.003.

  236. Vallarelli AF, et al. TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation. Oncotarget. 2016; https://doi.org/10.18632/oncotarget.10634.

  237. Bullock M, et al. ETS factor ETV5 activates the mutant telomerase reverse transcriptase promoter in thyroid cancer. Thyroid. 2019; https://doi.org/10.1089/thy.2018.0314.

  238. Li Y, Cheng HS, Chng WJ, Tergaonkar V, Cleaver JE. Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas. Proc Natl Acad Sci U S A. 2016; https://doi.org/10.1073/pnas.1611106113.

  239. Blasco MA, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997; https://doi.org/10.1016/S0092-8674(01)80006-4.

  240. Bodnar AG, et al. Extension of life-span by introduction of telomerase into normal human cells. Science (80-). 1998; https://doi.org/10.1126/science.279.5349.349.

  241. Coppé JP, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; https://doi.org/10.1371/journal.pbio.0060301.

  242. Wang E. Regulation of apoptosis resistance and ontogeny of age-dependent diseases. Exp Gerontol. 1997; https://doi.org/10.1016/S0531-5565(96)00156-8.

  243. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; https://doi.org/10.1146/annurev-physiol-030212-183653.

  244. Childs BG, Baker DJ, Kirkland JL, Campisi J, Deursen JM. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 2014; https://doi.org/10.15252/embr.201439245.

  245. Jeon OH, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23:775–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Storer M, et al. XSenescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell. 2013; https://doi.org/10.1016/j.cell.2013.10.041.

  247. Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer. 2015;15:397–408.

    Article  CAS  PubMed  Google Scholar 

  248. Jaskelioff M, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011; https://doi.org/10.1038/nature09603.

  249. Baker DJ, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Prata LGPL, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin Immunol. 2018; https://doi.org/10.1016/j.smim.2019.04.003.

  251. Coppé J-P, Desprez P-Y, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  252. Jeck WR, Siebold AP, Sharpless NE. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell. 2012;11:727–31.

    Article  CAS  PubMed  Google Scholar 

  253. Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Discovery, development, and future application of senolytics: theories and predictions. FEBS J. 2020; https://doi.org/10.1111/febs.15264.

  254. Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia. 2017; https://doi.org/10.1007/s00125-017-4372-6.

  255. Cabreiro F, et al. Metformin retards aging in C elegans by altering microbial folate and methionine metabolism. Cell. 2013; https://doi.org/10.1016/j.cell.2013.02.035.

  256. Martin-Montalvo A, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013; https://doi.org/10.1038/ncomms3192.

  257. Vasamsetti SB, et al. Metformin inhibits monocyte- To-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015; https://doi.org/10.2337/db14-1225.

  258. Hic LJ, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;

    Google Scholar 

  259. Justice JN, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019; https://doi.org/10.1016/j.ebiom.2018.12.052.

Download references

Acknowledgement

This work was supported by São Paulo Research Foundation (FAPESP, Fundação de Amparo a Pesquisa do Estado de São Paulo, Brazil, http://www.fapesp.br/), grant 2018/04375-2 to MINC and Federal Agency CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior—Brasil) to FMBT. Morea, E.G.O is a postdoctoral fellow from FAPESP (grant 2019/11496-3); BCDO and MES are doctoral fellows from FAPESP (grants 2019/25985-6, 2020/00316-1); SCP, VLS and VSF are undergraduate fellows from FAPESP (2018/25665-9, 2018/03095-6, 2018/03095-6). MINC is a PQ-CNPq fellow (grant 302433/2019-8). LKG is a postdoctoral fellow from CAPES; VP is a doctoral fellow from CAPES. FMBT is a PQ-CNPq fellow (grant 314375/2018-0). The funders had no role in study design, data collection, analysis, decision to publish or manuscript preparation.

Author information

Authors and Affiliations

  1. Postgraduate Program in Cellular and Molecular Biology, School of Health, Sciences and Life, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil

    Florencia Barbé-Tuana

  2. Laboratory of Immunobiology, School of Sciences, Life and Health, Pontifical Catholic University of Rio Grande do Sul – PUCRS, Porto Alegre, Brazil

    Florencia Barbé-Tuana

  3. Postgraduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil

    Lucas Kich Grun

  4. Postgraduate Program: Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil

    Vinícius Pierdoná

  5. Department of Chemical and Biological Sciences, Biosciences Institute, Sao Paulo State University, Botucatu, Brazil

    Beatriz Cristina Dias de Oliveira, Stephany Cacete Paiva, Mark Ewusi Shiburah, Vítor Luiz da Silva, Edna Gicela Ortiz Morea, Verônica Silva Fontes & Maria Isabel Nogueira Cano

Authors
  1. Florencia Barbé-Tuana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucas Kich Grun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vinícius Pierdoná
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beatriz Cristina Dias de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephany Cacete Paiva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Ewusi Shiburah
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vítor Luiz da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Edna Gicela Ortiz Morea
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Verônica Silva Fontes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maria Isabel Nogueira Cano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Florencia Barbé-Tuana .

Editor information

Editors and Affiliations

  1. Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil

    Luciana Amaral Haddad

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Barbé-Tuana, F. et al. (2021). Human Chromosome Telomeres. In: Haddad, L.A. (eds) Human Genome Structure, Function and Clinical Considerations. Springer, Cham. https://doi.org/10.1007/978-3-030-73151-9_7

Download citation

Publish with us

Policies and ethics

Search

Navigation