Telomeres are complex protective structures located at the ends of linear eukaryotic chromosomes. Their purpose is to prevent genomic instability. Research progress in telomere biology during the past decades has identified a network of telomeric transcripts of which the best-studied is TElomeric Repeat-containing RNA (TERRA). TERRA was shown to be important not only for the preservation of telomere homeostasis and genomic stability but also for the expression of hundreds of genes across the human genome. These findings added a new level of complexity to telomere biology. Herein we provide insights on the telomere transcriptome, its relevance for proper telomere function, and its implications in human pathology. We also discuss possible clinical opportunities of exosomal telomere transcripts detection as a biomarker in cancer precision medicine.

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer University Hospital Prague Czechia

Department of the Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czechia

Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czechia

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czechia

See more in PubMed

Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet (2008) 42:301–34. doi: 10.1146/annurev.genet.41.110306.130350 PubMed DOI

Shay JW, Wright WE. Telomeres and telomerase: Three decades of progress. Nat Rev Genet (2019) 20:299–309. doi: 10.1038/s41576-019-0099-1 PubMed DOI

Maciejowski J, de Lange T. Telomeres in cancer: Tumour suppression and genome instability. Nat Rev Mol Cell Biol (2017) 18:175–86. doi: 10.1038/nrm.2016.171 PubMed DOI PMC

Bryan TM. G-Quadruplexes at telomeres: Friend or foe? Molecules (2020) 25:E3686. doi: 10.3390/molecules25163686 PubMed DOI PMC

Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. . Mammalian telomeres end in a Large duplex loop. Cell (1999) 97:503–14. doi: 10.1016/S0092-8674(00)80760-6 PubMed DOI

Doksani Y, Wu JY, de Lange T, Zhuang X. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell (2013) 155:345–56. doi: 10.1016/j.cell.2013.09.048 PubMed DOI PMC

Srinivas N, Rachakonda S, Kumar R. Telomeres and telomere length: A general overview. Cancers (Basel) (2020) 12:E558. doi: 10.3390/cancers12030558 PubMed DOI PMC

de Lange T. Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev (2005) 19:2100–10. doi: 10.1101/gad.1346005 PubMed DOI

Court R, Chapman L, Fairall L, Rhodes D. How the human telomeric proteins TRF1 and TRF2 recognize telomeric DNA: A view from high-resolution crystal structures. EMBO Rep (2005) 6:39–45. doi: 10.1038/sj.embor.7400314 PubMed DOI PMC

Smith EM, Pendlebury DF, Nandakumar J. Structural biology of telomeres and telomerase. Cell Mol Life Sci (2020) 77:61–79. doi: 10.1007/s00018-019-03369-x PubMed DOI PMC

Bettin N, Oss Pegorar C, Cusanelli E. The emerging roles of TERRA in telomere maintenance and genome stability. Cells (2019) 8:E246. doi: 10.3390/cells8030246 PubMed DOI PMC

Lee SS, Bohrson C, Pike AM, Wheelan SJ, Greider CW. ATM Kinase is required for telomere elongation in mouse and human cells. Cell Rep (2015) 13:1623–32. doi: 10.1016/j.celrep.2015.10.035 PubMed DOI PMC

Wright WE, Shay JW. The two-stage mechanism controlling cellular senescence and immortalization. Exp Gerontol (1992) 27:383–9. doi: 10.1016/0531-5565(92)90069-c PubMed DOI

Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, et al. . Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J (2019) 38:e100492. doi: 10.15252/embj.2018100492 PubMed DOI PMC

Fouquerel E, Barnes RP, Uttam S, Watkins SC, Bruchez MP, Opresko PL. Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis. Mol Cell (2019) 75:117–130.e6. doi: 10.1016/j.molcel.2019.04.024 PubMed DOI PMC

Takai H, Smogorzewska A, de Lange T. DNA Damage foci at dysfunctional telomeres. Curr Biol (2003) 13:1549–56. doi: 10.1016/s0960-9822(03)00542-6 PubMed DOI

Qian Y, Chen X. Tumor suppression by p53: Making cells senescent. Histol Histopathol (2010) 25:515–26. doi: 10.14670/HH-25.515 PubMed DOI PMC

Brown JP, Wei W, Sedivy JM. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science (1997) 277:831–4. doi: 10.1126/science.277.5327.831 PubMed DOI

Wei W, Herbig U, Wei S, Dutriaux A, Sedivy JM. Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts. EMBO Rep (2003) 4:1061–6. doi: 10.1038/sj.embor.embor7400001 PubMed DOI PMC

Yuan X, Dai M, Xu D. Telomere-related markers for cancer. Curr Top Med Chem (2020) 20:410–32. doi: 10.2174/1568026620666200106145340 PubMed DOI PMC

Tardat M, Déjardin J. Telomere chromatin establishment and its maintenance during mammalian development. Chromosoma (2018) 127:3–18. doi: 10.1007/s00412-017-0656-3 PubMed DOI PMC

Rudenko G, Van der Ploeg LH. Transcription of telomere repeats in protozoa. EMBO J (1989) 8:2633–8. doi: 10.1002/j.1460-2075.1989.tb08403.x PubMed DOI PMC

Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science (2007) 318:798–801. doi: 10.1126/science.1147182 PubMed DOI

Schoeftner S, Blasco MA. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol (2008) 10:228–36. doi: 10.1038/ncb1685 PubMed DOI

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) 30:4808–17. doi: 10.1128/MCB.00460-10 PubMed DOI PMC

Montero JJ, López-Silanes I, Megías D, F Fraga M, Castells-García Á., Blasco MA. TERRA recruitment of polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin. Nat Commun (2018) 9:1548. doi: 10.1038/s41467-018-03916-3 PubMed DOI PMC

Chu H-P, Cifuentes-Rojas C, Kesner B, Aeby E, Lee HG, Wei C, et al. . TERRA RNA antagonizes ATRX and protects telomeres. Cell (2017) 170:86–101.e16. doi: 10.1016/j.cell.2017.06.017 PubMed DOI PMC

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) 134:11974–6. doi: 10.1021/ja305734x PubMed DOI PMC

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) 35:403–13. doi: 10.1016/j.molcel.2009.06.025 PubMed DOI PMC

Porro A, Feuerhahn S, Lingner J. TERRA-reinforced association of LSD1 with MRE11 promotes processing of uncapped telomeres. Cell Rep (2014) 6:765–76. doi: 10.1016/j.celrep.2014.01.022 PubMed DOI

Porro A, Feuerhahn S, Delafontaine J, Riethman H, Rougemont J, Lingner J. Functional characterization of the TERRA transcriptome at damaged telomeres. Nat Commun (2014) 5:5379. doi: 10.1038/ncomms6379 PubMed DOI PMC

Xu Y, Kaminaga K, Komiyama M. G-Quadruplex formation by human telomeric repeats-containing RNA in Na+ solution. J Am Chem Soc (2008) 130:11179–84. doi: 10.1021/ja8031532 PubMed DOI

Martadinata H, Heddi B, Lim KW, Phan AT. Structure of long human telomeric RNA (TERRA): G-quadruplexes formed by four and eight UUAGGG repeats are stable building blocks. Biochemistry (2011) 50:6455–61. doi: 10.1021/bi200569f PubMed DOI

Kim W, Shay JW. Long-range telomere regulation of gene expression: Telomere looping and telomere position effect over long distances (TPE-OLD). Differentiation (2018) 99:1–9. doi: 10.1016/j.diff.2017.11.005 PubMed DOI PMC

Yang D, Xiong Y, Kim H, He Q, Li Y, Chen R, et al. . Human telomeric proteins occupy selective interstitial sites. Cell Res (2011) 21:1013–27. doi: 10.1038/cr.2011.39 PubMed DOI PMC

Garrobo I, Marión RM, Domínguez O, Pisano DG, Blasco MA. Genome-wide analysis of in vivo TRF1 binding to chromatin restricts its location exclusively to telomeric repeats. Cell Cycle (2014) 13:3742–9. doi: 10.4161/15384101.2014.965044 PubMed DOI PMC

Simonet T, Zaragosi L-E, Philippe C, Lebrigand K, Schouteden C, Augereau A, et al. . The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats. Cell Res (2011) 21:1028–38. doi: 10.1038/cr.2011.40 PubMed DOI PMC

Mignon-Ravix C, Depetris D, Delobel B, Croquette M-F, Mattei M-G. A human interstitial telomere associates in vivo with specific TRF2 and TIN2 proteins. Eur J Hum Genet (2002) 10:107–12. doi: 10.1038/sj.ejhg.5200775 PubMed DOI

Kim W, Ludlow AT, Min J, Robin JD, Stafler G, Mender I, et al. . Regulation of the human telomerase gene TERT by telomere position effect-over long distances (TPE-OLD): Implications for aging and cancer. PloS Biol (2016) 14:e2000016. doi: 10.1371/journal.pbio.2000016 PubMed DOI PMC

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) 38:5797–806. doi: 10.1093/nar/gkq296 PubMed DOI PMC

Nagpal N, Agarwal S. Telomerase RNA processing: Implications for human health and disease. Stem Cells (2020) 75:117–30. doi: 10.1002/stem.3270 PubMed DOI PMC

Ng LJ, Cropley JE, Pickett HA, Reddel RR, Suter CM. Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription. Nucleic Acids Res (2009) 37:1152–9. doi: 10.1093/nar/gkn1030 PubMed DOI PMC

Chebly A, Ropio J, Baldasseroni L, Prochazkova-Carlotti M, Idrissi Y, Ferref J, et al. . Telomeric repeat-containing RNA (TERRA): A review of the literature and first assessment in cutaneous T-cell lymphomas. Genes (Basel) (2022) 13:539. doi: 10.3390/genes13030539 PubMed DOI PMC

Moravec M, Wischnewski H, Bah A, Hu Y, Liu N, Lafranchi L, et al. . TERRA promotes telomerase-mediated telomere elongation in Schizosaccharomyces pombe . EMBO Rep (2016) 17:999–1012. doi: 10.15252/embr.201541708 PubMed DOI PMC

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) 51:780–91. doi: 10.1016/j.molcel.2013.08.029 PubMed DOI

Lalonde M, Chartrand P. TERRA, a multifaceted regulator of telomerase activity at telomeres. J Mol Biol (2020) 432:4232–43. doi: 10.1016/j.jmb.2020.02.004 PubMed DOI

Pfeiffer V, Lingner J. TERRA promotes telomere shortening through exonuclease 1-mediated resection of chromosome ends. PloS Genet (2012) 8:e1002747. doi: 10.1371/journal.pgen.1002747 PubMed DOI PMC

Kwapisz M, Morillon A. Subtelomeric transcription and its regulation. J Mol Biol (2020) 432:4199–219. doi: 10.1016/j.jmb.2020.01.026 PubMed DOI PMC

Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, et al. . Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science (2015) 347:273–7. doi: 10.1126/science.1257216 PubMed DOI PMC

Feretzaki M, Renck Nunes P, Lingner J. Expression and differential regulation of human TERRA at several chromosome ends. RNA (2019) 25:1470–80. doi: 10.1261/rna.072322.119 PubMed DOI PMC

Silva B, Arora R, Bione S, Azzalin CM. TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells. Nat Commun (2021) 12:3760. doi: 10.1038/s41467-021-24097-6 PubMed DOI PMC

Barthel FP, Wei W, Tang M, Martinez-Ledesma E, Hu X, Amin SB, et al. . Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat Genet (2017) 49:349–57. doi: 10.1038/ng.3781 PubMed DOI PMC

Okamoto K, Seimiya H. Revisiting telomere shortening in cancer. Cells (2019) 8:E107. doi: 10.3390/cells8020107 PubMed DOI PMC

Hirashima K, Seimiya H. Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo . Nucleic Acids Res (2015) 43:2022–32. doi: 10.1093/nar/gkv063 PubMed DOI PMC

Hirashima K, Migita T, Sato S, Muramatsu Y, Ishikawa Y, Seimiya H. Telomere length influences cancer cell differentiation in vivo . Mol Cell Biol (2013) 33:2988–95. doi: 10.1128/MCB.00136-13 PubMed DOI PMC

Riethman H, Ambrosini A, Castaneda C, Finklestein J, Hu X-L, Mudunuri U, et al. . Mapping and initial analysis of human subtelomeric sequence assemblies. Genome Res (2004) 14:18–28. doi: 10.1101/gr.1245004 PubMed DOI PMC

Montero JJ, López de Silanes I, Graña O, Blasco MA. Telomeric RNAs are essential to maintain telomeres. Nat Commun (2016) 7:12534. doi: 10.1038/ncomms12534 PubMed DOI PMC

Fejzo MS, Anderson L, Chen H-W, Anghel A, Zhuo J, Anchoori R, et al. . ADRM1-amplified metastasis gene in gastric cancer. Genes Chromosomes Cancer (2015) 54:506–15. doi: 10.1002/gcc.22262 PubMed DOI

Rocha M, Zanardo EA, Dias AT, et al. . Cytogenomic changes in sporadic colorectal cancer and surrounding nonneoplastic tissues: The relevance of subtelomeric copy number variations (2021) (Accessed 25 January 2022).

Nishibuchi G, Déjardin J. The molecular basis of the organization of repetitive DNA-containing constitutive heterochromatin in mammals. Chromosome Res (2017) 25:77–87. doi: 10.1007/s10577-016-9547-3 PubMed DOI

de Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM, et al. . Structure and variability of human chromosome ends. Mol Cell Biol (1990) 10:518–27. doi: 10.1128/MCB.10.2.518 PubMed DOI PMC

Le Berre G, Hossard V, Riou J-F, Guieysse-Peugeot A-L. Repression of TERRA expression by subtelomeric DNA methylation is dependent on NRF1 binding. Int J Mol Sci (2019) 20:E2791. doi: 10.3390/ijms20112791 PubMed DOI PMC

Gonzalez-Vasconcellos I, Schneider R, Anastasov N, Alonso-Rodriguez S, Sanli-Bonazzi B, Fernández JL, et al. . The Rb1 tumour suppressor gene modifies telomeric chromatin architecture by regulating TERRA expression. Sci Rep (2017) 7:42056. doi: 10.1038/srep42056 PubMed DOI PMC

Tutton S, Azzam GA, Stong N, Vladimirova O, Wiedmer A, Monteith JA, et al. . Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres. EMBO J (2016) 35:193–207. doi: 10.15252/embj.201490880 PubMed DOI PMC

Vohhodina J, Goehring LJ, Liu B, Kong Q, Botchkarev VV, Jr, Huynh M, et al. . BRCA1 binds TERRA RNA and suppresses r-loop-based telomeric DNA damage. Nat Commun (2021) 12:3542. doi: 10.1038/s41467-021-23716-6 PubMed DOI PMC

Koskas S, Decottignies A, Dufour S, Pezet M, Verdel A, Vourc’h C, et al. . Heat shock factor 1 promotes TERRA transcription and telomere protection upon heat stress. Nucleic Acids Res (2017) 45:6321–33. doi: 10.1093/nar/gkx208 PubMed DOI PMC

Galigniana NM, Charó NL, Uranga R, Cabanillas AM, Piwien-Pilipuk G. Oxidative stress induces transcription of telomeric repeat-containing RNA (TERRA) by engaging PKA signaling and cytoskeleton dynamics. Biochim Biophys Acta Mol Cell Res (2020) 1867:118643. doi: 10.1016/j.bbamcr.2020.118643 PubMed DOI

Maestroni L, Reyes C, Vaurs M, Gachet Y, Tournier S, Géli V, et al. . Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells. Nucleic Acids Res (2020) 48:3029–41. doi: 10.1093/nar/gkaa043 PubMed DOI PMC

Cao H, Zhai Y, Ji X, Wang Y, Zhao J, Xing J, et al. . Noncoding telomeric repeat-containing RNA inhibits the progression of hepatocellular carcinoma by regulating telomerase-mediated telomere length. Cancer Sci (2020) 111:2789–802. doi: 10.1111/cas.14442 PubMed DOI PMC

Adishesh M, Alnafakh R, Baird DM, Jones RE, Simon S, Button L, et al. . Human endometrial carcinogenesis is associated with significant reduction in long non-coding RNA, TERRA. Int J Mol Sci (2020) 21:E8686. doi: 10.3390/ijms21228686 PubMed DOI PMC

Sampl S, Pramhas S, Stern C, Preusser M, Marosi C, Holzmann K. Expression of telomeres in astrocytoma WHO grade 2 to 4: TERRA level correlates with telomere length, telomerase activity, and advanced clinical grade. Trans Oncol (2012) 5:56–IN4. doi: 10.1593/tlo.11202 PubMed DOI PMC

Vitelli V, Falvo P, G. Nergadze S, Santagostino M, Khoriauli L, Pellanda P, et al. . Telomeric repeat-containing RNAs (TERRA) decrease in squamous cell carcinoma of the head and neck is associated with worsened clinical outcome. IJMS (2018) 19:274. doi: 10.3390/ijms19010274 PubMed DOI PMC

Deng Z, Wang Z, Xiang C, et al. . Formation of telomeric repeat-containing RNA (TERRA) foci in highly proliferating mouse cerebellar neuronal progenitors and medulloblastoma. J Cell Sci (2012) 125:jcs.108118. doi: 10.1242/jcs.108118 PubMed DOI PMC

Bae SU, Park W-J, Jeong WK, Baek SK, Lee H-W, Lee J-H. Prognostic impact of telomeric repeat-containing RNA expression on long-term oncologic outcomes in colorectal cancer. Medicine (2019) 98:e14932. doi: 10.1097/MD.0000000000014932 PubMed DOI PMC

McIlrath J, Bouffler SD, Samper E, Cuthbert A, Wojcik A, Szumiel I, et al. . Telomere length abnormalities in mammalian radiosensitive cells. Cancer Res (2001) 61:912–5. PubMed

Smirnova A, Gamba R, Khoriauli L, Vitelli V, Nergadze SG, Giulotto E. TERRA expression levels do not correlate with telomere length and radiation sensitivity in human cancer cell lines. Front Oncol (2013) 3:115. doi: 10.3389/fonc.2013.00115 PubMed DOI PMC

Nergadze SG, Farnung BO, Wischnewski H, Khoriauli L, Vitelli V, Chawla R, et al. . CpG-island promoters drive transcription of human telomeres. RNA (2009) 15:2186–94. doi: 10.1261/rna.1748309 PubMed DOI PMC

Voon HPJ, Wong LH. New players in heterochromatin silencing: histone variant H3.3 and the ATRX/DAXX chaperone. Nucleic Acids Res (2016) 44:1496–501. doi: 10.1093/nar/gkw012 PubMed DOI PMC

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. . DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science (2011) 331:1199–203. doi: 10.1126/science.1200609 PubMed DOI PMC

Nandakumar P, Mansouri A, Das S. The role of ATRX in glioma biology. Front Oncol (2017) 7:236. doi: 10.3389/fonc.2017.00236 PubMed DOI PMC

Clynes D, Goncalves T, Kent T, Shepherd S, Cunniffe S, Kim S, et al. . Induction of the ALT pathway requires loss of ATRX-DAXX in concert with genotoxic lesions at telomeres (2021) (Accessed 28 June 2022).

Li F, Deng Z, Zhang L, et al. . ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization(2019) (Accessed 1 July 2022). PubMed PMC

Wang Z, Deng Z, Dahmane N, Tsai K, Wang P, Williams DR, et al. . Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes. Proc Natl Acad Sci USA (2015) 112:E6293–6300. doi: 10.1073/pnas.1505962112 PubMed DOI PMC

Padron JG, Saito Reis CA, Kendal-Wright CE. The role of danger associated molecular patterns in human fetal membrane weakening. Front Physiol (2020) 11:602. doi: 10.3389/fphys.2020.00602 PubMed DOI PMC

Wang Z, Lieberman PM. The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes. RNA Biol (2016) 13:690–5. doi: 10.1080/15476286.2016.1203503 PubMed DOI PMC

Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, et al. . A senescent cell bystander effect: Senescence-induced senescence. Aging Cell (2012) 11:345–9. doi: 10.1111/j.1474-9726.2012.00795.x PubMed DOI PMC