Telomeric Repeat-Containing RNA (TERRA) and Human Diseases

Document Type : Review Article

Authors

1 MSc Student, Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease AND Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Assistant Professor, Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease AND Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Telomeres are the physical ends of linear chromosomes that maintain chromosomal stability. Loss of telomere function can lead to decrease in replication capacity, cellular senescence and progeria syndromes. In addition, cancer can be developed as a result of the genomic instability associated with telomere dysfunction. Till now, two types of telomere maintenance mechanism (TMM) have been known. The only two telomere maintenance mechanisms that have been described in mammalian cells are an enzymatic method that employs telomerase and recombination-based alternative lengthening of telomeres (ALT). In neoplasia, telomere maintenance mechanisms can be prognostic and may direct therapy in the future. Recently, a class of noncoding telomeric repeat-containing RNA (TERRA or TelRNA) transcripts has been transcribed from telomeres. Generally, increased TERRA transcription is associated with telomere shortening. In this review, we briefly evaluated the general principles behind telomere dysfunction. Moreover, the relationship between TERRA and disease has been described. Finally, TERRA potential in therapeutic approaches associated with defects in telomere function is studied.

Keywords


  1. Luke B, Lingner J. TERRA: telomeric repeat-containing RNA. EMBO J 2009; 28(17): 2503-10.
  2. McEachern MJ, Krauskopf A, Blackburn EH. Telomeres and their control. Annu Rev Genet 2000; 34: 331-58.
  3. Blackburn EH. Structure and function of telomeres. Nature 1991; 350(6319): 569-73.
  4. Kheirollahi M, Mehrazin M, Kamalian N, Mehdipour P. Alterations of telomere length in human brain tumors. Med Oncol 2011; 28(3): 864–70.
  5. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990; 345(6274): 458-60.
  6. Dejardin J, Kingston RE. Purification of proteins associated with specific genomic Loci. Cell 2009; 136(1): 175-86.
  7. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42: 301-34.
  8. Ottaviani A, Gilson E, Magdinier F. Telomeric position effect: from the yeast paradigm to human pathologies? Biochimie 2008; 90(1): 93-107.
  9. Blasco MA. The epigenetic regulation of mammalian telomeres. Nat Rev Genet 2007; 8(4): 299-309.
  10. Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 2008; 452(7186): 492-6.
  11. Yehezkel S, Segev Y, Viegas-Pequignot E, Skorecki K, Selig S. Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions. Hum Mol Genet 2008; 17(18): 2776-89.
  12. Blackburn EH, Greider CW, Szostak JW. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 2006; 12(10): 1133-8.
  13. Cech TR. Beginning to understand the end of the chromosome. Cell 2004; 116(2): 273-9.
  14. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279(5349): 349-52.
  15. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO. Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev 1999; 13(18): 2388-99.
  16. Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J Mol Biol 1992; 225(4): 951-60.
  17. 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(2): 518-27.
  18. Garcia-Cao M, O'Sullivan R, Peters AH, Jenuwein T, Blasco MA. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 2004; 36(1): 94-9.
  19. Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 2006; 8(4): 416-24.
  20. Baur JA, Zou Y, Shay JW, Wright WE. Telomere position effect in human cells. Science 2001; 292(5524): 2075-7.
  21. 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(5851): 798-801.
  22. Feuerhahn S, Iglesias N, Panza A, Porro A, Lingner J. TERRA biogenesis, turnover and implications for function. FEBS Lett 2010; 584(17): 3812-8.
  23. Luke B, Panza A, Redon S, Iglesias N, Li Z, Lingner J. The Rat1p 5' to 3' exonuclease degrades telomeric repeat-containing RNA and promotes telomere elongation in Saccharomyces cerevisiae. Mol Cell 2008; 32(4): 465-77.
  24. Solovei I, Gaginskaya ER, Macgregor HC. The arrangement and transcription of telomere DNA sequences at the ends of lampbrush chromosomes of birds. Chromosome Res 1994; 2(6): 460-70.
  25. Rudenko G, Van der Ploeg LH. Transcription of telomere repeats in protozoa. EMBO J 1989; 8(9): 2633-8.
  26. Morcillo G, Barettino D, Carmona MJ, Carretero MT, Diez JL. Telomeric DNA sequences differentially activated by heat shock in two Chironomus subspecies. Chromosoma 1988; 96(2): 139-44.
  27. Schoeftner S, Blasco MA. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 2008; 10(2): 228-36.
  28. Vrbsky J, Akimcheva S, Watson JM, Turner TL, Daxinger L, Vyskot B, et al. siRNA-mediated methylation of Arabidopsis telomeres. PLoS Genet 2010; 6(6): e1000986.
  29. 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(12): 2186-94.
  30. 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(20): 4808-17.
  31. Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002; 416(6880): 552-6.
  32. Schoeftner S, Blasco MA. Chromatin regulation and non-coding RNAs at mammalian telomeres. Semin Cell Dev Biol 2010; 21(2): 186-93.
  33. 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(17): 5797-806.
  34. Zhang LF, Ogawa Y, Ahn JY, Namekawa SH, Silva SS, Lee JT. Telomeric RNAs mark sex chromosomes in stem cells. Genetics 2009; 182(3): 685-98.
  35. Marion RM, Strati K, Li H, Tejera A, Schoeftner S, Ortega S, et al. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 2009; 4(2): 141-54.
  36. Chawla R, Azzalin CM. The telomeric transcriptome and SMG proteins at the crossroads. Cytogenet Genome Res 2008; 122(3-4): 194-201.
  37. Ciaudo C, Bourdet A, Cohen-Tannoudji M, Dietz HC, Rougeulle C, Avner P. Nuclear mRNA degradation pathway(s) are implicated in Xist regulation and X chromosome inactivation. PLoS Genet 2006; 2(6): e94.
  38. Shay JW, Pereira-Smith OM, Wright WE. A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 1991; 196(1): 33-9.
  39. Smogorzewska A, de Lange T. Different telomere damage signaling pathways in human and mouse cells. EMBO J 2002; 21(16): 4338-48.
  40. Prives C, Hall PA. The p53 pathway. J Pathol 1999; 187(1): 112-26.
  41. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266(5193): 2011-5.
  42. Kheirollahi M, Mehrazin M, Kamalian N, Mohammadi-asl J, Mehdipour P. Telomerase activity in human brain tumors: astrocytoma and meningioma. Cell Mol Neurobiol 2013; 33(4): 569-74.
  43. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985; 43(2 Pt 1): 405-13.
  44. Collins K. Mammalian telomeres and telomerase. Curr Opin Cell Biol 2000; 12(3): 378-83.
  45. Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR. Protein composition of catalytically active human telomerase from immortal cells. Science 2007; 315(5820): 1850-3.
  46. Ulaner GA, Giudice LC. Developmental regulation of telomerase activity in human fetal tissues during gestation. Mol Hum Reprod 1997; 3(9): 769-73.
  47. Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med 1997; 3(11): 1271-4.
  48. Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 1995; 14(17): 4240-8.
  49. Dunham MA, Neumann AA, Fasching CL, Reddel RR. Telomere maintenance by recombination in human cells. Nat Genet 2000; 26(4): 447-50.
  50. Grobelny JV, Kulp-McEliece M, Broccoli D. Effects of reconstitution of telomerase activity on telomere maintenance by the alternative lengthening of telomeres (ALT) pathway. Hum Mol Genet 2001; 10(18): 1953-61.
  51. Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res 1999; 59(17): 4175-9.
  52. Hakin-Smith V, Jellinek DA, Levy D, Carroll T, Teo M, Timperley WR, et al. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 2003; 361(9360): 836-8.
  53. Hung NA, Hsia H, Royds JA, Slatter TL. Telomere maintenance mechanisms: prognostic and therapeutic implications for the pathologist and oncologist. Open Journal of Pathology 2013; 3(1): 10-20.
  54. 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(4): 1152-9.
  55. 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. Transl Oncol 2012; 5(1): 56-65.
  56. Dashti S, Ashouri S, Kheirollahi M. Expression of TERRA in different grades of astrocytoma. J Isfahan Med Sch 2015; 32(317): 2333-42. [In Persian].
  57. Dashti S, Khorvash F, Salehi R, Mahzouni P, Koulivand L, Kheirollahi M. Expression of TERRA in human brain tumors. Eur J Oncol 2015. [In Press].
  58. Armanios M. Syndromes of telomere shortening. Annu Rev Genomics Hum Genet 2009; 10: 45-61.
  59. Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis 2010; 31(1): 9-18.
  60. Blackburn EH. Walking the walk from genes through telomere maintenance to cancer risk. Cancer Prev Res (Phila) 2011; 4(4): 473-5.
  61. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet 2011; 204(12): 635-45.
  62. Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res 2012; 730(1-2): 52-8.
  63. Walne AJ, Dokal I. Dyskeratosis Congenita: a historical perspective. Mech Ageing Dev 2008; 129(1-2): 48-59.
  64. Gu B, Bessler M, Mason PJ. Dyskerin, telomerase and the DNA damage response. Cell Cycle 2009; 8(1): 6-10.
  65. Kheirollahi M. Telomere, regulation and tumorigenesis. In: Mehdipour P, editor. Telomere territory and cancer. New York, NY: Springer; 2013. p. 55-98.
  66. Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 2009; 85(6): 823-32.
  67. O'Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 2010; 11(3): 171-81.
  68. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 2005; 102(44): 15960-4.
  69. Ehrlich M. The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin Immunol 2003; 109(1): 17-28.
  70. Iglesias N, Redon S, Pfeiffer V, Dees M, Lingner J, Luke B. Subtelomeric repetitive elements determine TERRA regulation by Rap1/Rif and Rap1/Sir complexes in yeast. EMBO Rep 2011; 12(6): 587-93.
  71. Colgin LM, Reddel RR. Telomere maintenance mechanisms and cellular immortalization. Curr Opin Genet Dev 1999; 9(1): 97-103.
  72. Flynn RL, Centore RC, O'Sullivan RJ, Rai R, Tse A, Songyang Z, et al. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 2011; 471(7339): 532-6.