1932

Abstract

Telomerase is the essential reverse transcriptase required for linear chromosome maintenance in most eukaryotes. Telomerase supplements the tandem array of simple-sequence repeats at chromosome ends to compensate for the DNA erosion inherent in genome replication. The template for telomerase reverse transcriptase is within the RNA subunit of the ribonucleoprotein complex, which in cells contains additional telomerase holoenzyme proteins that assemble the active ribonucleoprotein and promote its function at telomeres. Telomerase is distinct among polymerases in its reiterative reuse of an internal template. The template is precisely defined, processively copied, and regenerated by release of single-stranded product DNA. New specificities of nucleic acid handling that underlie the catalytic cycle of repeat synthesis derive from both active site specialization and new motif elaborations in protein and RNA subunits. Studies of telomerase provide unique insights into cellular requirements for genome stability, tissue renewal, and tumorigenesis as well as new perspectives on dynamic ribonucleoprotein machines.

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2017-06-20
2024-06-13
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Literature Cited

  1. Müller HJ. 1.  1938. The remaking of chromosomes. Collect. Net 13:181–98 [Google Scholar]
  2. McClintock B. 2.  1941. The stability of broken ends of chromosomes in Zea mays. Genetics 26:234–82 [Google Scholar]
  3. Blackburn EH, Gall JG. 3.  1978. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J. Mol. Biol. 120:33–53 [Google Scholar]
  4. Gilson E, Geli V. 4.  2007. How telomeres are replicated. Nat. Rev. Mol. Cell Biol. 8:825–38 [Google Scholar]
  5. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A. 5.  et al. 1999. Mammalian telomeres end in a large duplex loop. Cell 97:503–14 [Google Scholar]
  6. de Lange T. 6.  2010. How shelterin solves the telomere end-protection problem. Cold Spring Harb. Symp. Quant. Biol. 75:167–77 [Google Scholar]
  7. Lewis KA, Wuttke DS. 7.  2012. Telomerase and telomere-associated proteins: structural insights into mechanism and evolution. Structure 20:28–39 [Google Scholar]
  8. Baumann P, Price C. 8.  2010. Pot1 and telomere maintenance. FEBS Lett 584:3779–84 [Google Scholar]
  9. Schmutz I, de Lange T. 9.  2016. Shelterin. Curr. Biol. 26:R397–99 [Google Scholar]
  10. Price CM, Boltz KA, Chaiken MF, Stewart JA, Beilstein MA, Shippen DE. 10.  2010. Evolution of CST function in telomere maintenance. Cell Cycle 9:3157–65 [Google Scholar]
  11. Lloyd NR, Dickey TH, Hom RA, Wuttke DS. 11.  2016. Tying up the ends: plasticity in the recognition of single-stranded DNA at telomeres. Biochemistry 55:5326–40 [Google Scholar]
  12. Wellinger RJ, Zakian VA. 12.  2012. Everything you ever wanted to know about Saccharomyces cerevisiae telomeres: beginning to end. Genetics 191:1073–105 [Google Scholar]
  13. Biessmann H, Mason JM. 13.  1997. Telomere maintenance without telomerase. Chromosoma 106:63–69 [Google Scholar]
  14. de Lange T. 14.  2015. A loopy view of telomere evolution. Front. Genet. 6:321 [Google Scholar]
  15. Lambowitz AM, Belfort M. 15.  2015. Mobile bacterial group II introns at the crux of eukaryotic evolution. Microbiol. Spectr. 3:MDNA3–0050–2014 [Google Scholar]
  16. Blackburn EH, Greider CW, Szostak JW. 16.  2006. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat. Med. 12:1133–38 [Google Scholar]
  17. Greider CW, Blackburn EH. 17.  1989. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337:331–37 [Google Scholar]
  18. Greider CW, Blackburn EH. 18.  1985. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43:405–13 [Google Scholar]
  19. Zahler AM, Prescott DM. 19.  1988. Telomere terminal transferase activity in the hypotrichous ciliate Oxytricha nova and a model for replication of the ends of linear DNA molecules. Nucleic Acids Res 16:6953–72 [Google Scholar]
  20. Shippen-Lentz D, Blackburn EH. 20.  1989. Telomere terminal transferase activity from Euplotes crassus adds large numbers of TTTTGGGG repeats onto telomeric primers. Mol. Cell. Biol. 9:2761–64 [Google Scholar]
  21. Morin GB. 21.  1989. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59:521–29 [Google Scholar]
  22. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD. 22.  et al. 1994. Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–15 [Google Scholar]
  23. Aubert G. 23.  2014. Telomere dynamics and aging. Prog. Mol. Biol. Transl. Sci. 125:89–111 [Google Scholar]
  24. Hiyama E, Hiyama K. 24.  2007. Telomere and telomerase in stem cells. Br. J. Cancer 96:1020–24 [Google Scholar]
  25. Collins K, Mitchell JR. 25.  2002. Telomerase in the human organism. Oncogene 21:564–79 [Google Scholar]
  26. Armanios M, Blackburn EH. 26.  2012. The telomere syndromes. Nat. Rev. Genet. 13:693–704 [Google Scholar]
  27. Holohan B, Wright WE, Shay JW. 27.  2014. Telomeropathies: an emerging spectrum disorder. J. Cell Biol. 205:289–99 [Google Scholar]
  28. Stanley SE, Armanios M. 28.  2015. The short and long telomere syndromes: paired paradigms for molecular medicine. Curr. Opin. Genet. Dev. 33:1–9 [Google Scholar]
  29. Shay JW. 29.  2016. Role of telomeres and telomerase in aging and cancer. Cancer Discov 6:584–93 [Google Scholar]
  30. Hockemeyer D, Jaenisch R. 30.  2016. Induced pluripotent stem cells meet genome editing. Cell Stem. Cell 18:573–86 [Google Scholar]
  31. Nelson AD, Shippen DE. 31.  2015. Evolution of TERT-interacting lncRNAs: expanding the regulatory landscape of telomerase. Front. Genet. 6:277 [Google Scholar]
  32. Podlevsky JD, Chen JJ. 32.  2016. Evolutionary perspectives of telomerase RNA structure and function. RNA Biol 13:720–32 [Google Scholar]
  33. Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM. 33.  et al. 1997. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat. Genet. 17:498–502 [Google Scholar]
  34. Lendvay TS, Morris DK, Sah J, Balasubramamian B, Lundblad V. 34.  1996. Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics 144:1399–412 [Google Scholar]
  35. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR. 35.  1997. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276:561–67 [Google Scholar]
  36. Lue NF, Lin YC, Mian IS. 36.  2003. A conserved telomerase motif within the catalytic domain of telomerase reverse transcriptase is specifically required for repeat addition processivity. Mol. Cell Biol. 23:8440–49 [Google Scholar]
  37. Xie M, Podlevsky JD, Qi X, Bley CJ, Chen JJ. 37.  2010. A novel motif in telomerase reverse transcriptase regulates telomere repeat addition rate and processivity. Nucleic Acids Res 38:1982–96 [Google Scholar]
  38. Podlevsky JD, Bley CJ, Omana RV, Qi X, Chen JJ. 38.  2008. The telomerase database. Nucleic Acids Res 36:D339–43 [Google Scholar]
  39. Gillis AJ, Schuller AP, Skordalakes E. 39.  2008. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature 455:633–37 [Google Scholar]
  40. Mitchell M, Gillis A, Futahashi M, Fujiwara H, Skordalakes E. 40.  2010. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA. Nat. Struct. Mol. Biol. 17:513–18 [Google Scholar]
  41. Eckert B, Collins K. 41.  2012. Roles of telomerase reverse transcriptase N-terminal domain in assembly and activity of Tetrahymena telomerase holoenzyme. J. Biol. Chem. 287:12805–14 [Google Scholar]
  42. Wu RA, Dagdas YS, Yilmaz ST, Yildiz A, Collins K. 42.  2015. Single-molecule imaging of telomerase reverse transcriptase in human telomerase holoenzyme and minimal RNP complexes. eLife 4:e08363 [Google Scholar]
  43. Friedman KL, Cech TR. 43.  1999. Essential functions of amino-terminal domains in the yeast telomerase catalytic subunit revealed by selection for viable mutants. Genes Dev 13:2863–74 [Google Scholar]
  44. Robart AR, Collins K. 44.  2011. Human telomerase domain interactions capture DNA for TEN domain-dependent processive elongation. Mol. Cell 42:308–18 [Google Scholar]
  45. Egan ED, Collins K. 45.  2012. Biogenesis of telomerase ribonucleoproteins. RNA 18:1747–59 [Google Scholar]
  46. Podlevsky JD, Li Y, Chen JJ. 46.  2016. The functional requirement of two structural domains within telomerase RNA emerged early in eukaryotes. Nucleic Acids Res 44:209891–901 [Google Scholar]
  47. Zappulla DC, Goodrich K, Cech TR. 47.  2005. A miniature yeast telomerase RNA functions in vivo and reconstitutes activity in vitro. Nat. Struct. Mol. Biol. 12:1072–77 [Google Scholar]
  48. Mason M, Schuller A, Skordalakes E. 48.  2011. Telomerase structure function. Curr. Opin. Struct. Biol. 21:92–100 [Google Scholar]
  49. Zhang Q, Kim NK, Feigon J. 49.  2011. Architecture of human telomerase RNA. PNAS 108:20325–32 [Google Scholar]
  50. Huang J, Brown AF, Wu J, Xue J, Bley CJ. 50.  et al. 2014. Structural basis for protein-RNA recognition in telomerase. Nat. Struct. Mol. Biol. 21:507–12 [Google Scholar]
  51. Jansson LI, Akiyama BM, Ooms A, Lu C, Rubin SM, Stone MD. 51.  2015. Structural basis of template-boundary definition in Tetrahymena telomerase. Nat. Struct. Mol. Biol. 22:883–88 [Google Scholar]
  52. Feigon J, Chan H, Jiang J. 52.  2016. Integrative structural biology of Tetrahymena telomerase: insights into catalytic mechanism and interaction at telomeres. FEBS J 283:2044–50 [Google Scholar]
  53. Steitz TA. 53.  1999. DNA polymerases: structural diversity and common mechanisms. J. Biol. Chem. 274:17395–98 [Google Scholar]
  54. Collins K. 54.  2011. Single-stranded DNA repeat synthesis by telomerase. Curr. Opin. Chem. Biol. 15:643–48 [Google Scholar]
  55. Wang H, Blackburn EH. 55.  1997. De novo telomere addition by Tetrahymena telomerase in vitro. EMBO J 16:866–79 [Google Scholar]
  56. Melek M, Shippen DE. 56.  1996. Chromosome healing: spontaneous and programmed de novo telomere formation by telomerase. BioEssays 18:301–8 [Google Scholar]
  57. Miller MC, Collins K. 57.  2002. Telomerase recognizes its template by using an adjacent RNA motif. PNAS 99:6585–90 [Google Scholar]
  58. Jiang J, Chan H, Cash DD, Miracco EJ, Ogorzalek Loo RR. 58.  et al. 2015. Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions. Science 350:aab4070 [Google Scholar]
  59. Akiyama BM, Parks JW, Stone MD. 59.  2015. The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA-DNA hybrids. Nucleic Acids Res 43:5537–49 [Google Scholar]
  60. Qi X, Xie M, Brown AF, Bley CJ, Podlevsky JD, Chen JJ. 60.  2012. RNA/DNA hybrid binding affinity determines telomerase template-translocation efficiency. EMBO J 31:150–61 [Google Scholar]
  61. Wang H, Gilley D, Blackburn EH. 61.  1998. A novel specificity for the primer-template pairing requirement in Tetrahymena telomerase. EMBO J 17:1152–60 [Google Scholar]
  62. Wu RA, Collins K. 62.  2014. Human telomerase specialization for repeat synthesis by unique handling of primer-template duplex. EMBO J 33:921–35 [Google Scholar]
  63. Brown AF, Podlevsky JD, Qi X, Chen Y, Xie M, Chen JJ. 63.  2014. A self-regulating template in human telomerase. PNAS 111:11311–16 [Google Scholar]
  64. Wu RA, Collins K. 64.  2014. Sequence specificity of human telomerase. PNAS 111:11234–35 [Google Scholar]
  65. Berman AJ, Akiyama BM, Stone MD, Cech TR. 65.  2011. The RNA accordion model for template positioning by telomerase RNA during telomeric DNA synthesis. Nat. Struct. Mol. Biol. 18:1371–75 [Google Scholar]
  66. Shippen-Lentz D, Blackburn EH. 66.  1990. Functional evidence for an RNA template in telomerase. Science 247:546–52 [Google Scholar]
  67. Yang W, Lee YS. 67.  2015. A DNA-hairpin model for repeat-addition processivity in telomere synthesis. Nat. Struct. Mol. Biol. 22:844–47 [Google Scholar]
  68. Hardy CD, Schultz CS, Collins K. 68.  2001. Requirements for the dGTP-dependent repeat addition processivity of recombinant Tetrahymena telomerase. J. Biol. Chem. 276:4863–71 [Google Scholar]
  69. Förstemann K, Lingner J. 69.  2005. Telomerase limits the extent of base pairing between template RNA and telomeric DNA. EMBO Rep 6:361–66 [Google Scholar]
  70. Morin GB. 70.  1991. Recognition of a chromosome truncation site associated with α-thalassaemia by human telomerase. Nature 353:454–56 [Google Scholar]
  71. Collins K, Greider CW. 71.  1993. Nucleolytic cleavage and non-processive elongation catalyzed by Tetrahymena telomerase. Genes Dev 7:1364–76 [Google Scholar]
  72. Greider CW. 72.  1991. Telomerase is processive. Mol. Cell. Biol. 11:4572–80 [Google Scholar]
  73. Baran N, Haviv Y, Paul B, Manor H. 73.  2002. Studies on the minimal lengths required for DNA primers to be extended by the Tetrahymena telomerase: implications for primer positioning by the enzyme. Nucleic Acids Res 30:5570–78 [Google Scholar]
  74. Jacobs SA, Podell ER, Cech TR. 74.  2006. Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase. Nat. Struct. Mol. Biol. 13:218–25 [Google Scholar]
  75. Romi E, Baran N, Gantman M, Shmoish M, Min B. 75.  et al. 2007. High-resolution physical and functional mapping of the template adjacent DNA binding site in catalytically active telomerase. PNAS 104:8791–96 [Google Scholar]
  76. Doublie S, Sawaya MR, Ellenberger T. 76.  1999. An open and closed case for all polymerases. Structure 7:R31–35 [Google Scholar]
  77. Lee YS, Gao Y, Yang W. 77.  2015. How a homolog of high-fidelity replicases conducts mutagenic DNA synthesis. Nat. Struct. Mol. Biol. 22:298–303 [Google Scholar]
  78. Collins K. 78.  1999. Ciliate telomerase biochemistry. Annu. Rev. Biochem. 68:187–218 [Google Scholar]
  79. Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I. 79.  et al. 2001. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J 20:6958–68 [Google Scholar]
  80. Pascolo E, Wenz C, Lingner J, Hauel N, Priepke H. 80.  et al. 2002. Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate. J. Biol. Chem. 277:15566–72 [Google Scholar]
  81. Robart AR, Collins K. 81.  2010. Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants. J. Biol. Chem. 285:4375–86 [Google Scholar]
  82. Zaug AJ, Crary SM, Jesse Fioravanti M, Campbell K, Cech TR. 82.  2013. Many disease-associated variants of hTERT retain high telomerase enzymatic activity. Nucleic Acids Res 41:8969–78 [Google Scholar]
  83. Chang M, Arneric M, Lingner J. 83.  2007. Telomerase repeat addition processivity is increased at critically short telomeres in a Tel1-dependent manner in Saccharomyces cerevisiae. Genes Dev. 21:2485–94 [Google Scholar]
  84. Zhao Y, Abreu E, Kim J, Stadler G, Eskiocak U. 84.  et al. 2011. Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions. Mol. Cell 42:297–307 [Google Scholar]
  85. Kannan R, Helston RM, Dannebaum RO, Baumann P. 85.  2015. Diverse mechanisms for spliceosome-mediated 3′ end processing of telomerase RNA. Nat. Commun. 6:6104 [Google Scholar]
  86. Qi X, Rand DP, Podlevsky JD, Li Y, Mosig A. 86.  et al. 2015. Prevalent and distinct spliceosomal 3′-end processing mechanisms for fungal telomerase RNA. Nat. Commun. 6:6105 [Google Scholar]
  87. Gallardo F, Chartrand P. 87.  2008. Telomerase biogenesis: the long road before getting to the end. RNA Biol 5:212–15 [Google Scholar]
  88. Witkin KL, Collins K. 88.  2004. Holoenzyme proteins required for the physiological assembly and activity of telomerase. Genes Dev 18:1107–18 [Google Scholar]
  89. Min B, Collins K. 89.  2009. An RPA-related sequence-specific DNA-binding subunit of telomerase holoenzyme is required for elongation processivity and telomere maintenance. Mol. Cell 36:609–19 [Google Scholar]
  90. Stone MS, Mihalusova M, O'Connor CM, Prathapam R, Collins K, Zhuang X. 90.  2007. Stepwise protein-mediated RNA folding directs assembly of telomerase ribonucleoprotein. Nature 446:458–61 [Google Scholar]
  91. Singh M, Wang Z, Koo BK, Patel A, Cascio D. 91.  et al. 2012. Structural basis for telomerase RNA recognition and RNP assembly by the holoenzyme La family protein p65. Mol. Cell 47:16–26 [Google Scholar]
  92. Noël JF, Larose S, Abou Elela S, Wellinger RJ. 92.  2012. Budding yeast telomerase RNA transcription termination is dictated by the Nrd1/Nab3 non-coding RNA termination pathway. Nucleic Acids Res 40:5625–36 [Google Scholar]
  93. Box JA, Bunch JT, Tang W, Baumann P. 93.  2008. Spliceosomal cleavage generates the 3′ end of telomerase RNA. Nature 456:910–14 [Google Scholar]
  94. Nguyen D, Grenier St-Sauveur V, Bergeron D, Dupuis-Sandoval F, Scott MS, Bachand F. 94.  2015. A polyadenylation-dependent 3′ end maturation pathway is required for the synthesis of the human telomerase RNA. Cell Rep 13:2244–57 [Google Scholar]
  95. Tang W, Kannan R, Blanchette M, Baumann P. 95.  2012. Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes. Nature 484:260–64 [Google Scholar]
  96. Lemieux B, Laterreur N, Perederina A, Noel JF, Dubois ML. 96.  et al. 2016. Active yeast telomerase shares subunits with ribonucleoproteins RNase P and RNase MRP. Cell 165:1171–81 [Google Scholar]
  97. Mitchell JR, Cheng J, Collins K. 97.  1999. A box H/ACA small nucleolar RNA-like domain at the human telomerase RNA 3′ end. Mol. Cell. Biol. 19:567–76 [Google Scholar]
  98. Mitchell JR, Collins K. 98.  2000. Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase in vivo and in vitro. Mol. Cell 6:361–71 [Google Scholar]
  99. Massenet S, Bertrand E, Verheggen C. 99.  2016. Assembly and trafficking of box C/D and H/ACA snoRNPs. RNA Biol 2016:1–13 [Google Scholar]
  100. Stanley SE, Gable DL, Wagner CL, Carlile TM, Hanumanthu VS. 100.  et al. 2016. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis–emphysema. Sci. Transl. Med. 8:351ra107 [Google Scholar]
  101. Egan ED, Collins K. 101.  2012. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. Mol. Cell. Biol. 32:2428–39 [Google Scholar]
  102. Tseng CK, Wang HF, Burns AM, Schroeder MR, Gaspari M, Baumann P. 102.  2015. Human telomerase RNA processing and quality control. Cell Rep 13:2232–43 [Google Scholar]
  103. Stuart BD, Choi J, Zaidi S, Xing C, Holohan B. 103.  et al. 2015. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat. Genet. 47:512–17 [Google Scholar]
  104. Tummala H, Walne A, Collopy L, Cardoso S, de la Fuente J. 104.  et al. 2015. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J. Clin. Invest. 125:2151–60 [Google Scholar]
  105. Londono-Vallejo JA, Wellinger RJ. 105.  2012. Telomeres and telomerase dance to the rhythm of the cell cycle. Trends Biochem. Sci. 37:391–99 [Google Scholar]
  106. Schmidt JC, Cech TR. 106.  2015. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev 29:1095–105 [Google Scholar]
  107. Tucey TM, Lundblad V. 107.  2014. Regulated assembly and disassembly of the yeast telomerase quaternary complex. Genes Dev 28:2077–89 [Google Scholar]
  108. Gallardo F, Laterreur N, Wellinger RJ, Chartrand P. 108.  2012. Telomerase caught in the act: united we stand, divided we fall. RNA Biol 9:1139–43 [Google Scholar]
  109. Gallardo F, Laterreur N, Cusanelli E, Ouenzar F, Querido E. 109.  et al. 2011. Live cell imaging of telomerase RNA dynamics reveals cell cycle-dependent clustering of telomerase at elongating telomeres. Mol. Cell 44:819–27 [Google Scholar]
  110. Bajon E, Laterreur N, Wellinger RJ. 110.  2015. A single templating RNA in yeast telomerase. Cell Rep 12:441–48 [Google Scholar]
  111. Fu D, Collins K. 111.  2006. Human telomerase and Cajal body ribonucleoproteins share a unique specificity of Sm protein association. Genes Dev 20:531–36 [Google Scholar]
  112. Sexton AN, Collins K. 112.  2011. The 5′ guanosine tracts of human telomerase RNA are recognized by the G-quadruplex binding domain of the RNA helicase DHX36 and function to increase RNA accumulation. Mol Cell. Biol. 31:736–43 [Google Scholar]
  113. Vogan JM, Collins K. 113.  2015. Dynamics of human telomerase holoenzyme assembly and subunit exchange across the cell cycle. J. Biol. Chem. 290:21320–35 [Google Scholar]
  114. Yi X, Tesmer VM, Savre-Train I, Shay JW, Wright WE. 114.  1999. Both transcriptional and posttranscriptional mechanisms regulate human telomerase template RNA levels. Mol. Cell. Biol. 19:3989–97 [Google Scholar]
  115. Vogan JM, Zhang X, Youmans DT, Regalado SG, Johnson JZ. 115.  et al. 2016. Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies. eLife 5:e18221 [Google Scholar]
  116. Venteicher AS, Abreu EB, Meng Z, McCann KE, Terns RM. 116.  et al. 2009. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323:644–48 [Google Scholar]
  117. Tycowski KT, Shu MD, Kukoyi A, Steitz JA. 117.  2009. A conserved WD40 protein binds the Cajal body localization signal of scaRNP particles. Mol. Cell 34:47–57 [Google Scholar]
  118. Zhong F, Savage SA, Shkreli M, Giri N, Jessop L. 118.  et al. 2011. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev 25:11–16 [Google Scholar]
  119. Chen Y, Deng Z, Jiang S, Hu Q, Liu H. 119.  et al. 2015. Human cells lacking coilin and Cajal bodies are proficient in telomerase assembly, trafficking and telomere maintenance. Nucleic Acids Res 43:385–95 [Google Scholar]
  120. Schmidt JC, Zaug AJ, Cech TR. 120.  2016. Live cell imaging reveals the dynamics of telomerase recruitment to telomeres. Cell 166:1188–97 [Google Scholar]
  121. Moser BA, Nakamura TM. 121.  2009. Protection and replication of telomeres in fission yeast. Biochem. Cell Biol. 87:747–58 [Google Scholar]
  122. Hockemeyer D, Collins K. 122.  2015. Control of human telomerase action at telomeres. Nat. Struct. Mol. Biol. 22:848–52 [Google Scholar]
  123. Jiang J, Miracco EJ, Hong K, Eckert B, Chan H. 123.  et al. 2013. The architecture of Tetrahymena telomerase holoenzyme. Nature 496:187–92 [Google Scholar]
  124. Hong K, Upton H, Miracco EJ, Jiang J, Zhou ZH. 124.  et al. 2013. Tetrahymena telomerase holoenzyme assembly, activation, and inhibition by domains of the p50 central hub. Mol. Cell. Biol. 33:3962–71 [Google Scholar]
  125. Rao T, Lubin JW, Armstrong GS, Tucey TM, Lundblad V, Wuttke DS. 125.  2014. Structure of Est3 reveals a bimodal surface with differential roles in telomere replication. PNAS 111:214–18 [Google Scholar]
  126. Hu X, Liu J, Jun HI, Kim JK, Qiao F. 126.  2016. Multi-step coordination of telomerase recruitment in fission yeast through two coupled telomere-telomerase interfaces. eLife 5:e15470 [Google Scholar]
  127. Chu TW, D'Souza Y, Autexier C. 127.  2016. The insertion in fingers domain in human telomerase can mediate enzyme processivity and telomerase recruitment to telomeres in a TPP1-dependent manner. Mol. Cell. Biol. 36:210–22 [Google Scholar]
  128. Tong AS, Stern JL, Sfeir A, Kartawinata M, de Lange T. 128.  et al. 2015. ATM and ATR signaling regulate the recruitment of human telomerase to telomeres. Cell Rep 13:1633–46 [Google Scholar]
  129. Lee SS, Bohrson C, Pike AM, Wheelan SJ, Greider CW. 129.  2015. ATM kinase is required for telomere elongation in mouse and human cells. Cell Rep 13:1623–32 [Google Scholar]
  130. Upton HE, Hong K, Collins K. 130.  2014. Direct single-stranded DNA binding by Teb1 mediates the recruitment of Tetrahymena thermophila telomerase to telomeres. Mol. Cell Biol. 34:4200–12 [Google Scholar]
  131. Min B, Collins K. 131.  2010. Multiple mechanisms for elongation processivity within the reconstituted Tetrahymena telomerase holoenzyme. J. Biol. Chem. 285:16434–43 [Google Scholar]
  132. Upton HE, Chan H, Feigon J, Collins K. 132.  2017. Shared subunits of Tetrahymena telomerase holoenzyme and Replication Protein A have different functions in different cellular complexes. J. Biol. Chem. 292:217–28 [Google Scholar]
  133. Gao H, Cervantes RB, Mandell EK, Otero JH, Lundblad V. 133.  2007. RPA-like proteins mediate yeast telomere function. Nat. Struct. Mol. Biol. 14:208–14 [Google Scholar]
  134. Evans SK, Lundblad V. 134.  1999. Est1 and Cdc13 as comediators of telomerase access. Science 286:117–20 [Google Scholar]
  135. Nandakumar J, Cech TR. 135.  2013. Finding the end: recruitment of telomerase to telomeres. Nat. Rev. Mol. Cell Biol. 14:69–82 [Google Scholar]
  136. Sexton AN, Regalado SG, Lai CS, Cost GJ, O'Neil CM. 136.  et al. 2014. Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes Dev 28:1885–99 [Google Scholar]
  137. Chen LY, Redon S, Lingner J. 137.  2012. The human CST complex is a terminator of telomerase activity. Nature 488:540–44 [Google Scholar]
  138. Wan B, Tang T, Upton H, Shuai J, Zhou Y. 138.  et al. 2015. The Tetrahymena telomerase p75–p45–p19 subcomplex is a unique CST complex. Nat. Struct. Mol. Biol. 22:1023–26 [Google Scholar]
  139. Lue NF, Chan J, Wright WE, Hurwitz J. 139.  2014. The CDC13-STN1-TEN1 complex stimulates Pol α activity by promoting RNA priming and primase-to-polymerase switch. Nat. Commun. 5:5762 [Google Scholar]
  140. Ray S, Karamysheva Z, Wang L, Shippen DE, Price CM. 140.  2002. Interactions between telomerase and primase physically link the telomere and chromosome replication machinery. Mol. Cell Biol. 22:5859–68 [Google Scholar]
  141. Miyagawa K, Low RS, Santosa V, Tsuji H, Moser BA. 141.  et al. 2014. SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1(Tpp1) to modulate shelterin-Stn1 interaction in fission yeast. PNAS 111:5950–55 [Google Scholar]
  142. Garg M, Gurung RL, Mansoubi S, Ahmed JO, Dave A. 142.  et al. 2014. Tpz1TPP1 SUMOylation reveals evolutionary conservation of SUMO-dependent Stn1 telomere association. EMBO Rep 15:871–77 [Google Scholar]
  143. Wu P, Takai H, de Lange T. 143.  2012. Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150:39–52 [Google Scholar]
  144. Dai X, Huang C, Bhusari A, Sampathi S, Schubert K, Chai W. 144.  2010. Molecular steps of G-overhang generation at human telomeres and its function in chromosome end protection. EMBO J 29:2788–801 [Google Scholar]
  145. Hwang H, Buncher N, Opresko PL, Myong S. 145.  2012. POT1-TPP1 regulates telomeric overhang structural dynamics. Structure 20:1872–80 [Google Scholar]
  146. Loayza D, De Lange T. 146.  2003. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423:1013–18 [Google Scholar]
  147. Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P. 147.  et al. 2007. The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445:506–10 [Google Scholar]
  148. Greider CW. 148.  2016. Regulating telomere length from the inside out: the replication fork model. Genes Dev 30:1483–91 [Google Scholar]
  149. Lin KW, Zakian VA. 149.  2015. 21st century genetics: mass spectrometry of yeast telomerase. Cold Spring Harb. Symp. Quant. Biol. 80:111–16 [Google Scholar]
  150. Martinez P, Blasco MA. 150.  2015. Replicating through telomeres: a means to an end. Trends Biochem. Sci. 40:504–15 [Google Scholar]
  151. Moser BA, Subramanian L, Chang YT, Noguchi C, Noguchi E, Nakamura TM. 151.  2009. Differential arrival of leading and lagging strand DNA polymerases at fission yeast telomeres. EMBO J 28:810–20 [Google Scholar]
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