TERT Structure, Function, and Molecular Mechanisms

Telomerases: Chemistry, Biology, and Clinical Applications

Volumn , Issue , 2012, Pages 53-78

  Skordalakes, Emmanuel ^a   Lue, Neal F ^b  

^a WISTAR INSTITUTE   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

TER active participation, in polymerization reaction; TERT structure, template boundaries within TER molecule; TRBD domain in telomerase RNP, high affinity RNA interaction

Indexed keywords

EID: 84886183737     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781118268667.ch3     Document Type: Chapter

References (100)

1. Arai, K., Masutomi, K., Khurts, S., Kaneko, S., Kobayashi, K., and Murakami, S. (2002) Two independent regions of human telomerase reverse transcriptase are important for its oligomerization and telomerase activity. J. Biol. Chem. 277: 8538-8544.
2. Armanios, M., Chen, J.L., Chang, Y.P., Brodsky, R.A., Hawkins, A., Griffin, C.A., Eshleman, J.R., Cohen, A.R., Chakravarti, A., Hamosh, A., et al. (2005) Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl. Acad. Sci. USA. 102: 15960-15964.
3. Autexier, C., and Lue, N.F. (2006) The structure and function of telomerase reverse transcriptase. Annu. Rev. Biochem. 75: 493-517.
4. Bachand, F., and Autexier, C. (2001) Functional regions of human telomerase reverse transcriptase and human telomerase RNA required for telomerase activity and RNA-protein interactions. Mol. Cell. Biol. 21: 1888-1897.
5. Banik, S.S., Guo, C., Smith, A.C., Margolis, S.S., Richardson, D.A., Tirado, C.A., and Counter, C.M. (2002) C-terminal regions of the human telomerase catalytic subunit essential for in vivo enzyme activity. Mol. Cell. Biol. 22: 6234-6246.
6. Baran, N., Haviv, Y., Paul, B., and Manor, H. (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: 5570-5578.
7. Beattie, T.L., Zhou, W., Robinson, M.O., and Harrington, L. (2000) Polymerization defects within human telomerase are distinct from telomerase RNA and TEP1 binding. Mol. Biol. Cell. 11: 3329-3340.
8. Beese, L.S., Derbyshire, V., and Steitz, T.A. (1993) Structure of DNA polymerase I Klenow fragment bound to duplex DNA. Science. 260: 352-355.
9. Blasco, M.A., Funk, W., Villeponteau, B., and Greider, C.W. (1995) Functional characterization and developmental regulation of mouse telomerase RNA. Science. 269: 1267-1270.
10. Bosoy, D., and Lue, N. (2001) Functional analysis of conserved residues in the putative "finger" domain of telomerase reverse transcriptase. J. Biol. Chem. 276: 46305-46312.
11. Bosoy, D., Peng, Y., Mian, I., and Lue, N. (2003) Conserved N-terminal motifs of telomerase reverse transcriptase required for ribonucleoprotein assembly in vivo. J. Biol. Chem. 278: 3882-3890.
12. Box, J.A., Bunch, J.T., Zappulla, D.C., Glynn, E.F., and Baumann, P. (2008) A flexible template boundary element in the RNA subunit of fission yeast telomerase. J. Biol. Chem. 283: 24224-24233.
13. Bressanelli, S., Tomei, L., Rey, F.A., and De Francesco, R. (2002) Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides. J. Virol. 76: 3482-3492.
14. Bryan, T.M., Goodrich, K.J., and Cech, T.R. (2000) Telomerase RNA bound by protein motifs specific to telomerase reverse transcriptase. Mol. Cell. 6: 493-499.
15. Bryan, T.M., Sperger, J.M., Chapman, K.B., and Cech, T.R. (1998) Telomerase reverse transcriptase genes identified in Tetrahymena thermophila and Oxytricha trifallax. Proc. Natl. Acad. Sci. USA. 95: 8479-8484.
16. Cases-Gonzalez, C.E., Gutierrez-Rivas, M., and Menendez-Arias, L. (2000) Coupling ribose selection to fidelity of DNA synthesis. The role of Tyr-115 of human immunodeficiency virus type 1 reverse transcriptase. J. Biol. Chem. 275: 19759-19767.
17. Cech, T.R. (2009) Crawling out of the RNA world. Cell. 136: 599-602.
18. Chen, J., and Greider, C. (2003) Template boundary definition in mammalian telomerase. Genes Dev. 17: p2747-2752.
19. Collins K, Greider CW (1993) Tetrahymena telomerase catalyzes nucleolytic cleavage and nonprocessive elongation. Genes Dev. 7: 1364-1376.
20. de Lange, T. (2009) How telomeres solve the end-protection problem. Science. 326: 948-952.
21. Di Marco, S., Volpari, C., Tomei, L., Altamura, S., Harper, S., Narjes, F., Koch, U., Rowley, M., De Francesco, R., Migliaccio, G.,et al. (2005) Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J. Biol. Chem. 280: 29765-29770.
22. Ding, J., Das, K., Hsiou, Y., Sarafianos, S.G., Clark, A.D., Jr., Jacobo-Molina, A., Tantillo, C., Hughes, S.H., and Arnold, E. (1998) Structure and functional implications of the polymerase active site region in a complex of HIV-1 RT with a double-stranded DNA template-primer and an antibody Fab fragment at 2.8 A resolution. J. Mol. Biol. 284: 1095-1111.
23. Dokal, I., and Vulliamy, T. (2003) Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev. 17: 217-225.
24. Drosopoulos, W.C., and Prasad, V.R. (2007) The active site residue Valine 867 in human telomerase reverse transcriptase influences nucleotide incorporation and fidelity. Nucl. Acids Res. 35: 1155-1168.
25. Drosopoulos, W.C., and Prasad, V.R. (2009) The telomerase-specific T motif is a restrictive determinant of repetitive reverse transcription by human telomerase. Mol. Cell. Biol. 30: 447-459.
26. Figueiredo, L., Rocha, E., Mancio-Silva, L., Prevost, C., Hernandez-Verdun, D., and Scherf, A. (2005) The unusually large Plasmodium telomerase reverse-transcriptase localizes in a discrete compartment associated with the nucleolus. Nucl. Acids Res. 33: p1111-1122.
27. Finger, S.N., and Bryan, T.M. (2008) Multiple DNA-binding sites in Tetrahymena telomerase. Nucl. Acids Res. 36: 1260-1272.
28. Fogarty, P.F., Yamaguchi, H., Wiestner, A., Baerlocher, G.M., Sloand, E., Zeng, W.S., Read, E. J., Lansdorp, P.M., and Young, N.S. (2003) Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 362: 1628-1630.
29. Forstemann, K., and Lingner, J. (2005) Telomerase limits the extent of base pairing between template RNA and telomeric DNA. EMBO Rep. 6: p361-366.
30. Friedman, K., Heit, J., Long, D., and Cech, T. (2003) N-terminal domain of yeast telomerase reverse transcriptase: recruitment of Est3p to the telomerase complex. Mol. Biol. Cell. 14: 1-13.
31. Friedman, K.L., and Cech, T.R. (1999) Essential functions of amino-terminal domains in the yeast telomerase catalytic subunit revealed by selection for viable mutants. Genes Dev. 13: 2863-2874.
32. Gillis, A.J., Schuller, A.P., and Skordalakes, E. (2008) Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature. 455: 633-637.
33. Greider, C. (1991) Telomerase is processive. Mol. Cell. Biol. 11: 4572-4580.
34. Haering, C.H., Nakamura, T.M., Baumann, P., and Cech, T.R. (2000) Analysis of telomerase catalytic subunit mutants in vivo and in vitro in Schizosaccharomyces pombe. Proc. Natl. Acad. Sci. USA. 97: 6367-6372.
35. Hammond, P.W., and Cech, T.R. (1998) Euplotes telomerase: evidence for limited base-pairing during primer elongation and dGTP as an effector of translocation. Biochemistry. 37: 5162-5172.
36. Harrington LA, Greider CW. (1991) Telomerase primer specificity and chromosome healing. Nature. 353: 451-454.
37. Hossain, S., Singh, S., and Lue, N. (2002) Functional analysis of the c-terminal extension of telomerase reverse transcriptase. A putative "thumb" domain. J. Biol. Chem. 277: 36174-36180.
38. Huang, H., Chopra, R., Verdine, G.L., and Harrison, S.C. (1998) Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science. 282: 1669-1675.
39. Huard, S., Moriarty, T., and Autexier, C. (2003) The C terminus of the human telomerase reverse transcriptase is a determinant of enzyme processivity. Nucl. Acids Res. 31: 4059-4070.
40. Jacobo-Molina, A., Ding, J., Nanni, R.G., Clark, A.D., Jr., Lu, X., Tantillo, C., Williams, R.L., Kamer, G., Ferris, A.L., Clark, P., et al. (1993) Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc. Natl. Acad. Sci. USA 90: 6320-6324.
41. Jacobs, S.A., Podell, E.R., and Cech, T.R. (2006) Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase. Nat. Struct. Mol. Biol. 13: 218-225.
42. Johansson, E., and Macneill, S.A. (2010) The eukaryotic replicative DNA polymerases take shape. Trends Biochem. Sci. 35: 339-347.
43. Kohlstaedt, L.A., Wang, J., Friedman, J.M., Rice, P.A., and Steitz, T.A. (1992) Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 256: 1783-1790.
44. Lai, C., Miller, M., and Collins, K. (2002) Template boundary definition in Tetrahymena telomerase. Genes Dev. 16: 415-420.
45. Lai, C.K., Mitchell, J.R., and Collins, K. (2001) RNA binding domain of telomerase reverse transcriptase. Mol. Cell. Biol. 21: 990-1000.
46. Latrick, C.M., and Cech, T.R. (2010) POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. EMBO J. 29: 924-933.
47. Lee, J., Mandell, E.K., Tucey, T.M., Morris, D.K., and Lundblad, V. (2008) The Est3 protein associates with yeast telomerase through an OB-fold domain. Nat. Struct. Mol. Biol. 15: 990-997.
48. Lee, M.S., and Blackburn, E.H. (1993) Sequence-specific DNA primer effects on telomerase polymerization activity. Mol. Cell. Biol. 13: 6586-6599.
49. Lee, S.R., Wong, J.M., and Collins, K. (2003) Human telomerase reverse transcriptase motifs required for elongation of a telomeric substrate. J. Biol. Chem. 278: 52531-52536.
50. Lendvay, T.S., Morris, D.K., Sah, J., Balasubramanian, B., and Lundblad, V. (1996) Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics. 144: 1399-1412.
51. Liang, J., Yagasaki, H., Kamachi, Y., Hama, A., Matsumoto, K., Kato, K., Kudo, K., and Kojima, S. (2006) Mutations in telomerase catalytic protein in Japanese children with aplastic anemia. Haematologica. 91: 656-658.
52. Ling, H., Boudsocq, F., Woodgate, R., and Yang, W. (2001) Crystal structure of a Y-family DNA polymerase in action: a mechanism for error-prone and lesion-bypass replication. Cell. 107: 91-102.
53. Lingner, J., and Cech, T.R. (1996) Purification of telomerase from Euplotes aediculatis: requirement of a primer 3' overhang. Proc. Natl. Acad. Sci. USA. 93: 10712-10717.
54. Lingner, J., Hughes, T.R., Shevchenko, A., Mann, M., Lundblad, V., and Cech, T.R. (1997) Reverse transcriptase motifs in the catalytic subunit of telomerase. Science. 276: 561-567.
55. Lue, N. (2004) Adding to the ends: what makes telomerase processive and how important is it? Bioessays. 26: 955-962.
56. Lue, N. (2005) A physical and functional constituent of telomerase anchor site. J. Biol. Chem. 280: 26586-26591.
57. Lue, N., Lin, Y., and Mian, I. (2003) A conserved telomerase motif within the catalytic domain of telomerase reverse transcriptase is specifically required for repeat addition processivity. Mol. Cell. Biol. 23: 8440-8449.
58. Lue, N.F., and Li, Z. (2007) Modeling and structure function analysis of the putative anchor site of yeast telomerase. Nucl. Acids Res. 35: 5213-5222.
59. Malik, H.S., Burke, W.D., and Eickbush, T.H. (2000) Putative telomerase catalytic subunits from Giardia lamblia and Caenorhabditis elegans. Gene. 251: 101-108.
60. Meier, B., Clejan, I., Liu, Y., Lowden, M., Gartner, A., Hodgkin, J., and Ahmed, S. (2006) trt-1 is the Caenorhabditis elegans catalytic subunit of telomerase. PLoS Genet. 2: e18.
61. Miller, M.C., Liu, J.K., and Collins, K. (2000) Template definition by Tetrahymena telomerase reverse transcriptase. EMBO J. 19: 4412-4422.
62. Min, B., and Collins, K. (2009) An RPA-related sequence-specific DNA-binding subunit of telomerase holoenzyme is required for elongation processivity and telomere maintenance. Mol. Cell. 36: 609-619.
63. Mitchell, M., Gillis, A., Futahashi, M., Fujiwara, H., and Skordalakes, E. (2010) Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA. Nat. Struct. Mol. Biol. 17: 513-518.
64. Miyoshi, T., Kanoh, J., Saito, M., and Ishikawa, F. (2008) Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science. 320: 1341-1344.
65. Moriarty, T., Huard, S., Dupuis, S., and Autexier, C. (2002) Functional multimerization of human telomerase requires an RNA interaction domain in the N terminus of the catalytic subunit. Mol. Cell. Biol. 22: p1253-1265.
66. Moriarty, T.J., Marie-Egyptienne, D.T., and Autexier, C. (2005a). Regulation of 5' template usage and incorporation of noncognate nucleotides by human telomerase. RNA. 11: 1448-1460.
67. Moriarty, T.J., Ward, R.J., Taboski, M.A., and Autexier, C. (2005b). An anchor site-type defect in human telomerase that disrupts telomere length maintenance and cellular immortalization. Mol. Biol. Cell. 16: 3152-3161.
68. O'Connor, C., Lai, C., and Collins, K. (2005) Two purified domains of telomerase reverse transcriptase reconstitute sequence-specific interactions with RNA. J. Biol. Chem. 280: 17533-17539.
69. Osanai, M., Kojima, K.K., Futahashi, R., Yaguchi, S., and Fujiwara, H. (2006) Identification and characterization of the telomerase reverse transcriptase of Bombyx mori (silkworm) and Tribolium castaneum (flour beetle). Gene. 376: 281-289.
70. Paeschke, K., Juranek, S., Simonsson, T., Hempel, A., Rhodes, D., and Lipps, H.J. (2008) Telomerase recruitment by the telomere end binding protein-beta facilitates G-quadruplex DNA unfolding in ciliates. Nat. Struct. Mol. Biol. 15: 598-604.
71. Peng, Y., Mian, I.S., and Lue, N.F. (2001) Analysis of telomerase processivity: mechanistic similarity to HIV-1 reverse transcriptase and role in telomere maintenance. Mol. Cell. 7: 1201-1211.
72. Podlevsky, J.D., Bley, C.J., Omana, R.V., Qi, X., and Chen, J.J. (2008) The telomerase database. Nucl. Acids Res. 36: D339-343.
73. Robart, A.R., and Collins, K. (2010) Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants. J. Biol. Chem. 285: 4375-4386.
74. Rodgers, D.W., Gamblin, S.J., Harris, B.A., Ray, S., Culp, J.S., Hellmig, B., Woolf, D.J., Debouck, C., and Harrison, S.C. (1995) The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA. 92: 1222-1226.
75. Romi, E., Baran, N., Gantman, M., Shmoish, M., Min, B., Collins, K., and Manor, H. (2007) High-resolution physical and functional mapping of the template adjacent DNA binding site in catalytically active telomerase. Proc. Natl. Acad. Sci. USA. 104: 8791-8796.
76. Rouda, S., and Skordalakes, E. (2007) Structure of the RNA-binding domain of telomerase: implications for RNA recognition and binding. Structure. 15: 1403-1412.
77. Sarafianos, S.G., Clark, A.D., Jr., Das, K., Tuske, S., Birktoft, J.J., Ilankumaran, P., Ramesha, A. R., Sayer, J.M., Jerina, D.M., Boyer, P.L.,et al. (2002) Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J. 21: 6614-6624.
78. Sarafianos, S.G., Das, K., Tantillo, C., Clark, A.D., Jr., Ding, J., Whitcomb, J.M., Boyer, P.L., Hughes, S.H., and Arnold, E. (2001) Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO J. 20: 1449-1461.
79. Sealey, D.C., Zheng, L., Taboski, M.A., Cruickshank, J., Ikura, M., and Harrington, L.A. (2010) The N-terminus of hTERT contains a DNA-binding domain and is required for telomerase activity and cellular immortalization. Nucl. Acids Res. 38: 2019-2035.
80. Sekaran, V.G., Soares, J., and Jarstfer, M.B. (2009) Structures of telomerase subunits provide functional insights. Biochim. Biophys. Acta. 1804: 1190-1201.
81. Seto, A.G., Umansky, K., Tzfati, Y., Zaug, A.J., Blackburn, E.H., and Cech, T.R. (2003) A template-proximal RNA paired element contributes to Saccharomyces cerevisiae telo-merase activity. RNA. 9: 1323-1332.
82. Smith, R.A., Anderson, D.J., and Preston, B.D. (2006) Hypersusceptibility to substrate analogs conferred by mutations in human immunodeficiency virus type 1 reverse transcriptase. J. Virol. 80: 7169-7178.
83. Steitz, T. (1999) DNA polymerases: structural diversity and common mechanisms. J. Biol. Chem. 274: 17395-17398.
84. Steitz, T.A. (1997) DNA and RNA polymerases: structural diversity and common mechanisms. Harvey Lect. 93: 75-93.
85. Tantillo, C., Ding, J., Jacobo-Molina, A., Nanni, R.G., Boyer, P.L., Hughes, S.H., Pauwels, R., Andries, K., Janssen, P.A., and Arnold, E. (1994) Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J. Mol. Biol. 243: 369-387.
86. Tzfati, Y., Fulton, T.B., Roy, J., and Blackburn, E.H. (2000) Template boundary in a yeast telomerase specified by RNA structure. Science. 288: 863-867.
87. Vulliamy, T., Marrone, A., Dokal, I., and Mason, PJ. (2002) Association between aplastic anaemia and mutations in telomerase RNA. Lancet. 359: 2168-2170.
88. Vulliamy, T.J., Walne, A., Baskaradas, A., Mason, P.J., Marrone, A., and Dokal, I. (2005) Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol. Dis. 34: 257-263.
89. Vulliamy, T.J., Marrone, A., Knight S.W., Walne, A., Mason, PJ., Dokal, I. (2006) Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 107(7): 2680-2685.
90. Wang, F., Podell, E.R., Zaug, A.J., Yang, Y., Baciu, P., Cech, T.R., and Lei, M. (2007) The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature. 445: 506-510.
91. Wang, J., Sattar, A.K., Wang, C.C., Karam, J.D., Konigsberg, W.H., and Steitz, T.A. (1997) Crystal structure of a pol alpha family replication DNA polymerase from bacteriophage RB69. Cell. 89: 1087-1099.
92. Wyatt, H.D., Lobb, D.A., and Beattie, T.L. (2007) Characterization of physical and functional anchor site interactions in human telomerase. Mol. Cell. Biol. 27: 3226-3240.
93. Wyatt, H.D., Tsang, A.R., Lobb, D.A., and Beattie, T.L. (2009) Human telomerase reverse transcriptase (hTERT) Q169 is essential for telomerase function in vitro and in vivo. PLoS One. 4: e7176.
94. Xia, J., Peng, Y., Mian, I.S., and Lue, N.F. (2000) Identification of functionally important domains in the N-terminal region of telomerase reverse transcriptase. Mol. Cell. Biol. 20: 5196-5207.
95. Xie, M., Podlevsky, J.D., Qi, X., Bley, C.J., and Chen, J.J. (2010) A novel motif in telomerase reverse transcriptase regulates telomere repeat addition rate and processivity. Nucl. Acids Res. 38: 1982-1996.
96. Xin, H., Liu, D., Wan, M., Safari, A., Kim, H., Sun, W., O'Connor, M.S., and Songyang, Z. (2007) TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature. 445: 559-562.
97. Yamaguchi, H., Calado, R.T., Ly, H., Kajigaya, S., Baerlocher, G.M., Chanock, S.J., Lansdorp, P.M., and Young, N.S. (2005) Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352: 1413-1424.
98. Yu, E.Y., Wang, F., Lei, M., and Lue, N.F. (2008) A proposed OB-fold with a protein-interaction surface in Candida albicans telomerase protein Est3. Nat. Struct. Mol. Biol. 15: 985-989.
99. Zaug, A.J., Podell, E.R., and Cech, T.R. (2008) Mutation in TERT separates processivity from anchor-site function. Nat. Struct. Mol. Biol. 15: 870-872.
100. Zaug, A.J., Podell, E.R., Nandakumar, J., and Cech, T.R. (2010) Functional interaction between telomere protein TPP1 and telomerase. Genes Dev. 24: 613-622.