Human telomerase: Biogenesis, trafficking, recruitment, and activation

Genes and Development

Volumn 29, Issue 11, 2015, Pages 1095-1105

  Schmidt, Jens C ^a   Cech, Thomas R ^a  

^a UNIVERSITY OF COLORADO   (United States)

Author keywords

Biogenesis; Cancer; Recruitment; Telomerase; Telomere; Trafficking

Indexed keywords

RIBONUCLEOPROTEIN; TELOMERASE; TELOMERASE REVERSE TRANSCRIPTASE;

BIOGENESIS; COILED BODY; ENZYME ACTIVATION; ENZYME LOCALIZATION; ENZYME STRUCTURE; ENZYME SYNTHESIS; ENZYMOLOGY; HUMAN; PRIORITY JOURNAL; REVIEW; TELOMERE HOMEOSTASIS; BIOSYNTHESIS; METABOLISM; PHYSIOLOGY; PROTEIN MULTIMERIZATION; PROTEIN TRANSPORT;

EUKARYOTA;

ENZYME ACTIVATION; HUMANS; PROTEIN MULTIMERIZATION; PROTEIN TRANSPORT; TELOMERASE;

EID: 84932184510     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.263863.115     Document Type: Review

References (111)

1. Abreu E, Aritonovska E, Reichenbach P, Cristofari G, Culp B, Terns RM, Lingner J, Terns MP. 2010. TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol Cell Biol 30: 2971–2982.
2. Armanios M, Blackburn EH. 2012. The telomere syndromes. Nat Rev Genet 13: 693–704.
3. Armbruster BN, Banik SS, Guo C, Smith AC, Counter CM. 2001. N-terminal domains of the human telomerase catalytic subunit required for enzyme activity in vivo. Mol Cell Biol 21: 7775–7786.
4. Armbruster BN, Linardic CM, Veldman T, Bansal NP, Downie DL, Counter CM. 2004. Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1. Mol Cell Biol 24: 3552–3561.
5. Armstrong CA, Pearson SR, Amelina H, Moiseeva V, Tomita K. 2014. Telomerase activation after recruitment in fission yeast. Curr Biol 24: 2006–2011.
6. Baumann P, Cech TR. 2001. Pot1, the putative telomere endbinding protein in fission yeast and humans. Science 292: 1171–1175.
7. Blackburn EH. 2005. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett 579: 859–862.
8. Blackburn EH, Collins K. 2011. Telomerase: an RNPenzyme synthesizes DNA. Cold Spring Harb Perspect Biol 3.
9. Borah S, Xi L, Zaug AJ, Powell NM, Dancik GM, Cohen SB, Costello JC, Theodorescu D, Cech TR. 2015. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347: 1006–1010.
10. Bryan TM, Goodrich KJ, Cech TR. 2003. Tetrahymena telomerase is active as a monomer. Mol Biol Cell 14: 4794–4804.
11. Cech TR. 2004. Beginning to understand the end of the chromosome. Cell 116: 273–279.
12. Chen L-Y, Redon S, Lingner J. 2012. The human CST complex is a terminator of telomerase activity. Nature 488: 540–544.
13. Chung J, Khadka P, Chung IK. 2012. Nuclear import of hTERT requires a bipartite nuclear localization signal and Akt-mediated phosphorylation. J Cell Sci 125: 2684–2697.
14. Dalby AB, Hofr C, Cech TR. 2015. Contributions of the TELpatch amino acid cluster on TPP1 to telomericDNAsynthesis by human telomerase. J Mol Biol 427: 1291–1303.
15. Darzacq X, Kittur N, Roy S, Shav-Tal Y, Singer RH, Meier UT. 2006. StepwiseRNPassembly at the site of H/ACARNAtranscription in human cells. J Cell Biol 173: 207–218.
16. Denchi EL, de Lange T. 2007. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448: 1068–1071.
17. Doksani Y, Wu JY, de Lange T, Zhuang X. 2013. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell 155: 345–356.
18. Egan ED, Collins K. 2010. Specificity and stoichiometry of subunit interactions in the human telomerase holoenzyme assembled in vivo. Mol Cell Biol 30: 2775–2786.
19. Egan ED, Collins K. 2012a. Biogenesis of telomerase ribonucleoproteins. RNA 18: 1747–1759.
20. Egan ED, Collins K. 2012b. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. Mol Cell Biol 32: 2428–2439.
21. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J. 1995. The RNA component of human telomerase. Science 269: 1236–1241.
22. Freund A, Zhong FL, Venteicher AS, Meng Z, Veenstra TD, Frydman J, Artandi SE. 2014. Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1. Cell 159: 1389–1403.
23. Fu D, Collins K. 2003. Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs. Mol Cell 11: 1361–1372.
24. Gallardo F, Olivier C, Dandjinou AT, Wellinger RJ, Chartrand P. 2008. TLC1 RNA nucleo–cytoplasmic trafficking links telomerase biogenesis to its recruitment to telomeres. EMBO J 27: 748–757.
25. Gillis AJ, Schuller AP, Skordalakes E. 2008. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature 455: 633–637.
26. Girard C, Verheggen C, Neel H, Cammas A, Vagner S, Soret J, Bertrand E, Bordonné R. 2008. Characterization of a short isoform of human Tgs1 hypermethylase associating with small nucleolar ribonucleoprotein core proteins and produced by limited proteolytic processing. J Biol Chem 283: 2060–2069.
27. Greider CW. 1991. Telomerase is processive. Mol Cell Biol 11: 4572–4580.
28. Harkisheimer M, Mason M, Shuvaeva E, Skordalakes E. 2013. A motif in the vertebrate telomerase N-terminal linker of TERT contributes to RNA binding and telomerase activity and processivity. Structure 21: 1870–1878.
29. Heidenreich B, Rachakonda PS, Hemminki K, Kumar R. 2014. TERT promoter mutations in cancer development. Curr Opin Genet Dev 24: 30–37.
30. Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, Trager JB, Morin GB, Toft DO, Shay JW, et al. 1999. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev 13: 817–826.
31. Hong K, Upton H, Miracco EJ, Jiang J, Zhou ZH, Feigon J, Collins K. 2013. Tetrahymena telomerase holoenzyme assembly, activation, and inhibition by domains of the p50 central hub. Mol Cell Biol 33: 3962–3971.
32. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, et al. 2013. TERT promoter mutations in familial and sporadic melanoma. Science 339: 959–961.
33. Houghtaling BR, Cuttonaro L, Chang W, Smith S. 2004.Adynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol 14: 1621–1631.
34. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. 2013. Highly recurrent TERT promoter mutations in human melanoma. Science 339: 957–959.
35. Huang J, Brown AF, Wu J, Xue J, Bley CJ, Rand DP, Wu L, Zhang R, Chen JJ-L, Lei M. 2014. Structural basis for protein-RNA recognition in telomerase. Nat Struct Mol Biol 21: 507–512.
36. Hwang H, Buncher N, Opresko PL, Myong S. 2012. POT1–TPP1 regulates telomeric overhang structural dynamics. Structure 20: 1872–1880.
37. Hwang H, Opresko P, Myong S. 2014. Single-molecule real-time detection of telomerase extension activity. Sci Rep 4: 6391.
38. Jacobs SA, Podell ER, Cech TR. 2006. Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase. Nat Struct Mol Biol 13: 218–225.
39. Jády BE, Bertrand E, Kiss T. 2004. Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body-specific localization signal. J Cell Biol 164: 647–652.
40. Jády BE, Richard P, Bertrand E, Kiss T. 2006. Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres. Mol Biol Cell 17: 944–954.
41. Jiang J, Miracco EJ, Hong K, Eckert B, Chan H, Cash DD, Min B, Zhou ZH, Collins K, Feigon J. 2013. The architecture of Tetrahymena telomerase holoenzyme. Nature 496: 187–192.
42. Jun H-I, Liu J, Jeong H, Kim J-K, Qiao F. 2013. Tpz1 controls a telomerase- nonextendible telomeric state and coordinates switching to an extendible state via Ccq1. Genes Dev 27: 1917–1931.
43. Jurczyluk J, Nouwens AS, Holien JK, Adams TE, Lovrecz GO, Parker MW, Cohen SB, Bryan TM. 2011. Direct involvement of the TEN domain at the active site of human telomerase. Nucleic Acids Res 39: 1774–1788.
44. King TH, Decatur WA, Bertrand E, Maxwell ES, Fournier MJ. 2001. A well-connected and conserved nucleoplasmic helicase is required for production of box C/D and H/ACA snoRNAs and localization of snoRNP proteins. Mol Cell Biol 21: 7731–7746.
45. Kiss T, Fayet-Lebaron E, Jády BE. 2010. Box H/ACA small ribonucleoproteins. Mol Cell 37: 597–606.
46. Kocak H, Ballew BJ, Bisht K, Eggebeen R, Hicks BD, Suman S, O’Neil A, Giri N, et al. NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group 2014. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev 28: 2090–2102.
47. Lai CK, Mitchell JR, Collins K. 2001. RNA binding domain of telomerase reverse transcriptase. Mol Cell Biol 21: 990–1000.
48. Latrick CM, Cech TR. 2010. POT1–TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. EMBO J 29: 924–933.
49. Lee J, Mandell EK, Tucey TM, Morris DK, Lundblad V. 2008. The Est3 protein associates with yeast telomerase through an OBfold domain. Nat Struct Mol Biol 15: 990–997.
50. Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. 1992. Telomere end-replication problem and cell aging. J Mol Biol 225: 951–960.
51. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR. 1997. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276: 561–567.
52. Liu D, Safari A, O’Connor MS, Chan DW, Laegeler A, Qin J, Songyang Z. 2004. PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol 6: 673–680.
53. Min B, Collins K. 2009. An RPA-related sequence-specific DNAbinding subunit of telomerase holoenzyme is required for elongation processivity and telomere maintenance. Mol Cell 36: 609–619.
54. Min B, Collins K. 2010. Multiple mechanisms for elongation processivity within the reconstituted Tetrahymena telomerase holoenzyme. J Biol Chem 285: 16434–16443.
55. Mitchell JR, Collins K. 2000. Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase. Mol Cell 6: 361–371.
56. Mitchell JR, Cheng J, Collins K. 1999. A box H/ACA small nucleolar RNA-like domain at the human telomerase RNA 3′ end. Mol Cell Biol 19: 567–576.
57. Miyoshi T, Kanoh J, Saito M, Ishikawa F. 2008. Fission yeast Pot1–Tpp1 protects telomeres and regulates telomere length. Science 320: 1341–1344.
58. Morris DK, Lundblad V. 1997. Programmed translational frameshifting in a gene required for yeast telomere replication. Curr Biol 7: 969–976.
59. Moser BA, Chang Y-T, Kosti J, Nakamura TM. 2011. Tel1ATM and Rad3ATR kinases promote Ccq1–Est1 interaction to maintain telomeres in fission yeast. Nat Struct Mol Biol 18: 1408–1413.
60. Mozdy AD, Cech TR. 2006. Low abundance of telomerase in yeast: implications for telomerase haploinsufficiency. RNA 12: 1721–1737.
61. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR. 1997. Telomerase catalytic subunit homologs from fission yeast and human. Science 277: 955–959.
62. Nandakumar J, Cech TR. 2013. Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol 14: 69–82.
63. Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, Cech TR. 2012. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492: 285–289.
64. Palm W, de Lange T. 2008. How shelterin protects mammalian telomeres. Annu Rev Genet 42: 301–334.
65. Pennock E, Buckley K, Lundblad V. 2001. Cdc13 delivers separate complexes to the telomere for end protection and replication. Cell 104: 387–396.
66. Rao T, Lubin JW, Armstrong GS, Tucey TM, Lundblad V, Wuttke DS. 2014. Structure of Est3 reveals a bimodal surface with differential roles in telomere replication. Proc Natl Acad Sci 111: 214–218.
67. Redon S, Reichenbach P, Lingner J. 2007. Protein–RNA and protein– protein interactions mediate association of human EST1A/SMG6 with telomerase. Nucleic Acids Res 35: 7011–7022.
68. Redon S, Reichenbach P, Lingner J. 2010. The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res 38: 5797–5806.
69. Reichenbach P, Höss M, Azzalin CM, Nabholz M, Bucher P, Lingner J. 2003. A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed. Curr Biol 13: 568–574.
70. Richard P, Darzacq X, Bertrand E, Jády BE, Verheggen C, Kiss T. 2003. A common sequence motif determines the Cajal bodyspecific localization of box H/ACA scaRNAs. EMBO J 22: 4283–4293.
71. Robart AR, Collins K. 2011. Human telomerase domain interactions capture DNA for TEN domain-dependent processive elongation. Mol Cell 42: 308–318.
72. Rouda S, Skordalakes E. 2007. Structure of the RNA-binding domain of telomerase: implications for RNA recognition and binding. Structure 15: 1403–1412.
73. Sauerwald A, Sandin S, Cristofari G, Scheres SHW, Lingner J, Rhodes D. 2013. Structure of active dimeric human telomerase. Nat Struct Mol Biol 20: 454–460.
74. Schmidt JC, Dalby AB, Cech TR. 2014. Identification of human TERT elements necessary for telomerase recruitment to telomeres. Elife 3: e03563.
75. Schoeftner S, Blasco MA. 2008. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 10: 228–236.
76. Seto AG, Zaug AJ, Sobel SG, Wolin SL, Cech TR. 1999. Saccharomyces cerevisiae telomerase is an Sm small nuclear ribonucleoprotein particle. Nature 401: 177–180.
77. Seto AG, Livengood AJ, Tzfati Y, Blackburn EH, Cech TR. 2002.A bulged stem tethers Est1p to telomerase RNA in budding yeast. Genes Dev 16: 2800–2812.
78. Sexton AN, Youmans DT, Collins K. 2012. Specificity requirements for human telomere protein interaction with telomerase holoenzyme. J Biol Chem 287: 34455–34464.
79. Sexton AN, Regalado SG, Lai CS, Cost GJ, O’Neil CM, Urnov FD, Gregory PD, Jaenisch R, Collins K, Hockemeyer D. 2014. Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes Dev 28: 1885–1899.
80. Shay JW, Wright WE. 2011. Role of telomeres and telomerase in cancer. Semin Cancer Biol 21: 349–353.
81. Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L. 2003. Functional conservation of the telomerase protein Est1p in humans. Curr Biol 13: 698–704.
82. Stellwagen AE, Haimberger ZW, Veatch JR, Gottschling DE. 2003. Ku interacts with telomeraseRNA to promote telomere addition at native and broken chromosome ends. Genes Dev 17: 2384–2395.
83. Stern JL, Zyner KG, Pickett HA, Cohen SB, Bryan TM. 2012. Telomerase recruitment requires both TCAB1 and Cajal bodies independently. Mol Cell Biol 32: 2384–2395.
84. Stewart SA, Weinberg RA. 2006. Telomeres: cancer to human aging. Annu Rev Cell Dev Biol 22: 531–557.
85. Talley JM, DeZwaan DC, Maness LD, Freeman BC, Friedman KL. 2011. Stimulation of yeast telomerase activity by the ever shorter telomere 3 (Est3) subunit is dependent on direct interaction with the catalytic protein Est2. J Biol Chem 286: 26431–26439.
86. Tejera AM, Stagno d’Alcontres M, Thanasoula M, Marion RM, Martinez P, Liao C, Flores JM, Tarsounas M, Blasco MA. 2010. TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice. Dev Cell 18: 775–789.
87. Theimer CA, Feigon J. 2006. Structure and function of telomerase RNA. Curr Opin Struct Biol 16: 307–318.
88. Tomita K, Cooper JP. 2008. Fission yeast Ccq1 is telomerase recruiter and local checkpoint controller. Genes Dev 22: 3461–3474.
89. Tomlinson RL, Ziegler TD, Supakorndej T, Terns RM, Terns MP. 2006. Cell cycle-regulated trafficking of human telomerase to telomeres. Mol Biol Cell 17: 955–965.
90. Tomlinson RL, Abreu EB, Ziegler T, Ly H, Counter CM, Terns RM, Terns MP. 2008. Telomerase reverse transcriptase is required for the localization of telomerase RNA to cajal bodies and telomeres in human cancer cells. Mol Biol Cell 19: 3793–3800.
91. Tucey TM, Lundblad V. 2014. Regulated assembly and disassembly of the yeast telomerase quaternary complex. Genes Dev 28: 2077–2089.
92. Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE. 2008. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell 132: 945–957.
93. Venteicher AS, Abreu EB, Meng Z, McCann KE, Terns RM, Veenstra TD, Terns MP, Artandi SE. 2009.A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323: 644–648.
94. Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P, Cech TR, Lei M. 2007. The POT1–TPP1 telomere complex is a telomerase processivity factor. Nature 445: 506–510.
95. Wu RA, Collins K. 2014. Human telomerase specialization for repeat synthesis by unique handling of primer-template duplex. EMBO J 33: 921–935.
96. Wu P, Takai H, de Lange T. 2012. Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150: 39–52.
97. Xi L, Cech TR. 2014. Inventory of telomerase components in human cells reveals multiple subpopulations of hTR and hTERT. Nucleic Acids Res 42: 8565–8577.
98. Xin H, Liu D, Wan M, Safari A, Kim H, Sun W, O’Connor MS, Songyang Z. 2007. TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. Nature 445: 559–562.
99. Yamazaki H, Tarumoto Y, Ishikawa F. 2012. Tel1(ATM) and Rad3 (ATR) phosphorylate the telomere protein Ccq1 to recruit telomerase and elongate telomeres in fission yeast. Genes Dev 26: 241–246.
100. Ye JZ-S, Donigian JR, van Overbeek M, Loayza D, Luo Y, Krutchinsky AN, Chait BT, de Lange T. 2004. TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem 279: 47264–47271.
101. Yu EY, Wang F, Lei M, Lue NF. 2008. A proposed OB-fold with a protein-interaction surface in Candida albicans telomerase protein Est3. Nat Struct Mol Biol 15: 985–989.
102. Zaug AJ, Podell ER, Cech TR. 2005. Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proc Natl Acad Sci 102: 10864–10869.
103. Zaug AJ, Podell ER, Nandakumar J, Cech TR. 2010. Functional interaction between telomere protein TPP1 and telomerase. Genes Dev 24: 613–622.
104. Zaug AJ, Crary SM, Jesse Fioravanti M, Campbell K, Cech TR. 2013. Many disease-associated variants of hTERT retain high telomerase enzymatic activity. Nucleic Acids Res 41: 8969–8978.
105. Zeng Z, Min B, Huang J, Hong K, Yang Y, Collins K, Lei M. 2011. Structural basis for Tetrahymena telomerase processivity factor Teb1 binding to single-stranded telomeric-repeat DNA. Proc Natl Acad Sci 108: 20357–20361.
106. Zhang Q, Kim N-K, Feigon J. 2011. Architecture of human telomerase RNA. Proc Natl Acad Sci 108: 20325–20332.
107. Zhang Y, Chen L-Y, Han X, Xie W, Kim H, Yang D, Liu D, Songyang Z. 2013. Phosphorylation of TPP1 regulates cell cycledependent telomerase recruitment. Proc Natl Acad Sci 110: 5457–5462.
108. Zhao Y, Sfeir AJ, Zou Y, Buseman CM, Chow TT, Shay JW, Wright WE. 2009.Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells. Cell 138: 463–475.
109. Zhong F, Savage SA, Shkreli M, Giri N, Jessop L, Myers T, Chen R, Alter BP, Artandi SE. 2011. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev 25: 11–16.
110. Zhong FL, Batista LFZ, Freund A, Pech MF, Venteicher AS, Artandi SE. 2012. TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 150: 481–494.
111. Zhu X, Kumar R, Mandal M, Sharma N, Sharma HW, Dhingra U, Sokoloski JA, Hsiao R, Narayanan R. 1996. Cell cycle-dependent modulation of telomerase activity in tumor cells. Proc Natl Acad Sci 93: 6091–6095.