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  • Review Article
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Orchestrating nucleic acid–protein interactions at chromosome ends: telomerase mechanisms come into focus

Nature Structural & Molecular Biology volume 30, pages 878–890 (2023)Cite this article

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Abstract

Telomerase is a special reverse transcriptase ribonucleoprotein dedicated to the synthesis of telomere repeats that protect chromosome ends. Among reverse transcriptases, telomerase is unique in using a stably associated RNA with an embedded template to synthesize a specified sequence. Moreover, it is capable of iteratively copying the same template region (repeat addition processivity) through multiple rounds of RNA–DNA unpairing and reannealing, that is, the translocation reaction. Biochemical analyses of telomerase over the past 3 decades in protozoa, fungi and mammals have identified structural elements that underpin telomerase mechanisms and have led to models that account for the special attributes of telomerase. Notably, these findings and models can now be interpreted and adjudicated through recent cryo-EM structures of Tetrahymena and human telomerase holoenzyme complexes in association with substrates and regulatory proteins. Collectively, these structures reveal the intricate protein–nucleic acid interactions that potentiate telomerase’s unique translocation reaction and clarify how this enzyme reconfigures the basic reverse transcriptase scaffold to craft a polymerase dedicated to the synthesis of telomere DNA. Among the many new insights is the resolution of the telomerase ‘anchor site’ proposed more than 3 decades ago. The structures also highlight the nearly universal conservation of a protein–protein interface between an oligonucleotide/oligosaccharide-binding (OB)-fold regulatory protein and the telomerase catalytic subunit, which enables spatial and temporal regulation of telomerase function in vivo. In this Review, we discuss key features of the structures in combination with relevant functional analyses. We also examine conserved and divergent aspects of telomerase mechanisms as gleaned from studies in different model organisms.

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Fig. 1: Telomerase structure and the basic reaction cycle.
Fig. 2: Three-way interactions between the OBRP and the TEN domain and IFD of TERT.
Fig. 3: The interactions between TERT and 5′ telomere DNA within the telomerase complex.
Fig. 4: Regulation of the RNA–DNA hybrid and flanking nucleic acid conformation by telomerase motifs and comparison to conventional RTs.
Fig. 5: Summary models of telomerase mechanism and regulation and comparison to standard RTs.

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Data availability

The data generated and/or analyzed during the current study are included within the paper and its Supplementary Information or are available from the corresponding author upon reasonable request.

Code availability

The ColabFold modeling software is available at GitHub.

References

  1. de Lange, T. A loopy view of telomere evolution. Front. Genet. 6, 321 (2015).

    PubMed  PubMed Central  Google Scholar 

  2. Garavis, M., Gonzalez, C. & Villasante, A. On the origin of the eukaryotic chromosome: the role of noncanonical DNA structures in telomere evolution. Genome Biol. Evol. 5, 1142–1150 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. Blackburn, E. H., Epel, E. S. & Lin, J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350, 1193–1198 (2015).

    CAS  PubMed  Google Scholar 

  4. Blasco, M. A. Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Genet. 6, 611–622 (2005).

    CAS  PubMed  Google Scholar 

  5. Jafri, M. A., Ansari, S. A., Alqahtani, M. H. & Shay, J. W. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med. 8, 69 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Armanios, M. The role of telomeres in human disease. Annu. Rev. Genomics Hum. Genet. 23, 363–381 (2022).

    Google Scholar 

  7. Bonnell, E., Pasquier, E. & Wellinger, R. J. Telomere replication: solving multiple end replication problems. Front. Cell Dev. Biol. 9, 668171 (2021).

    PubMed  PubMed Central  Google Scholar 

  8. Lue, N. F. Evolving linear chromosomes and telomeres: a C-strand-centric view. Trends Biochem. Sci. 43, 314–326 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Lim, C. J. & Cech, T. R. Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization. Nat. Rev. Mol. Cell Biol. 22, 283–298 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu, R. A., Upton, H. E., Vogan, J. M. & Collins, K. Telomerase mechanism of telomere synthesis. Annu. Rev. Biochem. 86, 439–460 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Autexier, C. & Lue, N. The structure and function of telomerase reverse transcriptase. Annu. Rev. Biochem. 75, 493–517 (2006).

    CAS  PubMed  Google Scholar 

  12. Liu, B. et al. Structure of active human telomerase with telomere shelterin protein TPP1. Nature 604, 578–583 (2022). Report of cryo-EM structures (3.5-Å and 3.7-Å resolutions) of DNA-bound human telomerase holoenzyme in complex with or without TPP1 that highlight the three-way TPP1–TEN–IFDTRAP interface and reveal a 4-bp RNA–DNA duplex in the catalytic center.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Nguyen, T. H. D. et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature 557, 190–195 (2018). Report of cryo-EM structures (8.2-Å and 7.7-Å resolutions) of substrate-bound human telomerase holoenzyme showing two RNA-tethered lobes consisting of a catalytic core and a biogenesis module.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Schmidt, J. C. & Cech, T. R. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. 29, 1095–1105 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. MacNeil, D. E., Bensoussan, H. J. & Autexier, C. Telomerase regulation from beginning to the end. Genes 7, 64 (2016).

    PubMed  PubMed Central  Google Scholar 

  16. Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985).

    CAS  PubMed  Google Scholar 

  17. Morin, G. B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521–529 (1989).

    CAS  PubMed  Google Scholar 

  18. Lingner, J. & Cech, T. R. Purification of telomerase from Euplotes aediculatus: requirement of a 3′ overhang. Proc. Natl Acad. Sci. USA 93, 10712–10717 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959 (1997).

    CAS  PubMed  Google Scholar 

  20. Collins, K. & Gandhi, L. The reverse transcriptase component of the Tetrahymena telomerase ribonucleoprotein complex. Proc. Natl Acad. Sci. USA 95, 8485–8490 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakamura, T. M. & Cech, T. R. Reversing time: origin of telomerase. Cell 92, 587–590 (1998).

    CAS  PubMed  Google Scholar 

  22. Fitzgerald, M. S. et al. Disruption of the telomerase catalytic subunit gene from Arabidopsis inactivates telomerase and leads to a slow loss of telomeric DNA. Proc. Natl Acad. Sci. USA 96, 14813–14818 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Malik, H. S., Burke, W. D. & Eickbush, T. H. Putative telomerase catalytic subunits from Giardia lamblia and Caenorhabditis elegans. Gene 251, 101–108 (2000).

    CAS  PubMed  Google Scholar 

  24. Singer, M. S. & Gottschling, D. E. TLC1: template RNA component of Saccharomyces cerevisiae telomerase. Science 266, 404–409 (1994).

    CAS  PubMed  Google Scholar 

  25. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    CAS  PubMed  Google Scholar 

  26. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    CAS  PubMed  Google Scholar 

  27. de Lange, T. Shelterin-mediated telomere protection. Annu. Rev. Genet. 52, 223–247 (2018).

    PubMed  Google Scholar 

  28. Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    CAS  PubMed  Google Scholar 

  29. Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996).

    CAS  PubMed  Google Scholar 

  30. Mitchell, J. R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).

    CAS  PubMed  Google Scholar 

  31. Greider, C. W. Telomerase is processive. Mol. Cell. Biol. 11, 4572–4580 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Autexier, C. & Greider, C. W. Boundary elements of the Tetrahymena telomerase RNA template and alignment domains. Genes Dev. 15, 2227–2239 (1995).

    Google Scholar 

  33. Lai, C. K., Miller, M. C. & Collins, K. Template boundary definition in Tetrahymena telomerase. Genes Dev. 16, 415–420 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Tzfati, Y., Fulton, T. B., Roy, J. & Blackburn, E. H. Template boundary in a yeast telomerase specified by RNA structure. Science 288, 863–867 (2000).

    CAS  PubMed  Google Scholar 

  35. Podlevsky, J. D. & Chen, J. J. Evolutionary perspectives of telomerase RNA structure and function. RNA Biol. 13, 720–732 (2016).

    PubMed  PubMed Central  Google Scholar 

  36. Brown, A. F. et al. A self-regulating template in human telomerase. Proc. Natl Acad. Sci. USA 111, 11311–11316 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Jacobs, S. A., Podell, E. R. & Cech, T. R. Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase. Nat. Struct. Mol. Biol. 13, 218–225 (2006).

    CAS  PubMed  Google Scholar 

  38. Romi, E. et al. 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 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Collins, K. & Greider, C. W. Tetrahymena telomerase catalyzes nucleolytic cleavage and nonprocessive elongation. Genes Dev. 7, 1364–1376 (1993).

    CAS  PubMed  Google Scholar 

  40. Harrington, L. A. & Greider, C. W. Telomerase primer specificity and chromosome healing. Nature 353, 451–454 (1991).

    CAS  PubMed  Google Scholar 

  41. Lee, M. S. & Blackburn, E. H. Sequence-specific DNA primer effects on telomerase polymerization activity. Mol. Cell. Biol. 13, 6586–6599 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Morin, G. B. Recognition of a chromosome truncation site associated with α-thalassaemia by human telomerase. Nature 353, 454–456 (1991).

    CAS  PubMed  Google Scholar 

  43. Lue, N. F., Lin, Y. C. & Mian, I. S. 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 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Xie, M., Podlevsky, J. D., Qi, X., Bley, C. J. & Chen, J. J. A novel motif in telomerase reverse transcriptase regulates telomere repeat addition rate and processivity. Nucleic Acids Res. 38, 1982–1996 (2010).

    CAS  PubMed  Google Scholar 

  45. Jiang, J. et al. Structure of telomerase with telomeric DNA. Cell 173, 1179–1190 (2018). Report of a 4.8-Å-resolution cryo-EM structure of T. thermophila telomerase bound to telomeric DNA, revealing an independent structural module composed of the TEN domain and IFDTRAP, which forms a partial lid over the TERT ring; this unique ring-plus-lid conformation of TERT provides the structural underpinning for telomerase to accomplish processive telomere DNA synthesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang, Y., Gallagher-Jones, M., Susac, L., Song, H. & Feigon, J. A structurally conserved human and Tetrahymena telomerase catalytic core. Proc. Natl Acad. Sci. USA 117, 31078–31087 (2020). Using multiple sequence alignments and statistical coupling analysis on all identified TERTs, this study finds that the two β-strands implicated in the TEN–IFDTRAP interaction represent two of the most well-conserved, TERT-specific sequence motifs that can serve as a signature for archetypal telomerases.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hong, K. et al. Tetrahymena telomerase holoenzyme assembly, activation, and inhibition by domains of the p50 central hub. Mol. Cell. Biol. 33, 3962–3971 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Armstrong, C. A., Pearson, S. R., Amelina, H., Moiseeva, V. & Tomita, K. Telomerase activation after recruitment in fission yeast. Curr. Biol. 24, 2006–2011 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Talley, J. M., DeZwaan, D. C., Maness, L. D., Freeman, B. C. & Friedman, K. L. 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 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang, F. et al. The Pot1–TPP1 telomere complex is a telomerase processivity factor. Nature 445, 506–510 (2007).

    CAS  PubMed  Google Scholar 

  51. Gillis, A. J., Schuller, A. P. & Skordalakes, E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature 455, 633–637 (2008).

    CAS  PubMed  Google Scholar 

  52. Cohn, M. & Blackburn, E. H. Telomerase in yeast. Science 269, 396–400 (1995).

    CAS  PubMed  Google Scholar 

  53. Sekne, Z., Ghanim, G. E., van Roon, A. M. & Nguyen, T. H. D. Structural basis of human telomerase recruitment by TPP1–POT1. Science 375, 1173–1176 (2022). Report of cryo-EM structures (3.2-Å and 3.9-Å resolutions) of DNA-bound human telomerase holoenzyme in complex with TPP1 or TPP1–POT1 that highlight the three-way TPP1–TEN–IFDTRAP interface and a path for telomeric DNA from POT1 to the catalytic center with contacts to TEN, IFD, motif 3 and the CTE.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ghanim, G. E. et al. Structure of human telomerase holoenzyme with bound telomeric DNA. Nature 593, 449–453 (2021). Report of cryo-EM structures (3.8-Å and 3.4-Å resolutions) of human telomerase holoenzyme bound to telomeric DNA revealing the presence of a histone H2A–H2B dimer in the catalytic core and a detailed structure of the dyskerin–dyskerin interface.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. He, Y. et al. Structures of telomerase at several steps of telomere repeat synthesis. Nature 593, 454–459 (2021). Cryo-EM structures (3.3-Å, 4.4-Å and 3.8-Å resolutions) of T. thermophila telomerase with telomeric DNA at different steps of nucleotide addition, providing evidence for the maintenance of a short 4-bp RNA–DNA duplex during successive nucleotide addition and supporting a role of the catalytic core in anchor site function.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wan, F. et al. Zipper head mechanism of telomere synthesis by human telomerase. Cell Res. 31, 1275–1290 (2021). Characterization of a 3.54-Å-resolution structure of the catalytic module of human telomerase with a 24-nucleotide DNA species in combination with molecular dynamic simulation, which revealed the role of Leu980 in the thumb helix in acting as a ‘zipper head’ to limit the RNA–DNA duplex at the active site to just three canonical base pairs.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. He, Y. & Feigon, J. Telomerase structural biology comes of age. Curr. Opin. Struct. Biol. 76, 102446 (2022).

    CAS  PubMed  Google Scholar 

  58. Nguyen, T. H. D. Structural biology of human telomerase: progress and prospects. Biochem. Soc. Trans. 49, 1927–1939 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Smith, E. M., Pendlebury, D. F. & Nandakumar, J. Structural biology of telomeres and telomerase. Cell. Mol. Life Sci. 77, 61–79 (2020).

    CAS  Google Scholar 

  60. Lue, N. F. Plasticity of telomere maintenance mechanisms in yeast. Trends Biochem. Sci. 35, 8–17 (2010).

    CAS  PubMed  Google Scholar 

  61. Grill, S., Tesmer, V. M. & Nandakumar, J. The N terminus of the OB domain of telomere protein TPP1 is critical for telomerase action. Cell Rep. 22, 1132–1140 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hu, X., Liu, J., Jun, H. I., Kim, J. K. & Qiao, F. Multi-step coordination of telomerase recruitment in fission yeast through two coupled telomere–telomerase interfaces. eLife 5, e15470 (2016).

    PubMed  PubMed Central  Google Scholar 

  63. Nandakumar, J. et al. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492, 285–289 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Sexton, A. N., Youmans, D. T. & Collins, K. Specificity requirements for human telomere protein interaction with telomerase holoenzyme. J. Biol. Chem. 287, 34455–34464 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Zaug, A. J., Podell, E. R., Nandakumar, J. & Cech, T. R. Functional interaction between telomere protein TPP1 and telomerase. Genes Dev. 24, 613–622 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhong, F. L. et al. TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 150, 481–494 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Jiang, J. et al. The architecture of Tetrahymena telomerase holoenzyme. Nature 496, 187–192 (2013). Report of a cryo-EM structure (25-Å resolution) of a telomerase holoenzyme revealing an extensive network of protein associations, the interaction of p50 with the catalytic core of T. thermophila telomerase and the identification of p50 as functionally equivalent to human TPP1 in regulating enzyme processivity.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Lee, J., Mandell, E. K., Tucey, T. M., Morris, D. K. & Lundblad, V. The Est3 protein associates with yeast telomerase through an OB-fold domain. Nat. Struct. Mol. Biol. 15, 990–997 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Yu, E. Y., Wang, F., Lei, M. & Lue, N. F. A proposed OB-fold with a protein-interaction surface in Candida albicans telomerase protein Est3. Nat. Struct. Mol. Biol. 15, 985–989 (2008).

    PubMed  PubMed Central  Google Scholar 

  70. Schmidt, J. C., Dalby, A. B. & Cech, T. R. Identification of human TERT elements necessary for telomerase recruitment to telomeres. eLife 3, e03563 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Min, B. & Collins, K. An RPA-related sequence-specific DNA-binding subunit of telomerase holoenzyme is required for elongation processivity and telomere maintenance. Mol. Cell 36, 609–619 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Jiang, J. et al. Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions. Science 350, aab4070 (2015). Report of cryo-EM structures (9.4-Å and 8.9-Å resolutions) of the Tetrahymena telomerase holoenzyme, revealing the N-terminal, functional domain of p50 to be an OB fold juxtaposed to the TERT protein and presenting evidence that IFD independently contacts p50 and the TEN domain.

    PubMed  PubMed Central  Google Scholar 

  73. Chu, T. W., D’Souza, Y. & Autexier, C. 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, 210–222 (2016).

    CAS  PubMed  Google Scholar 

  74. Tesmer, V. M., Smith, E. M., Danciu, O., Padmanaban, S. & Nandakumar, J. Combining conservation and species-specific differences to determine how human telomerase binds telomeres. Proc. Natl Acad. Sci. USA 116, 26505–26515 (2019).

  75. D’Souza, Y., Chu, T. W. & Autexier, C. A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization. Mol. Biol. Cell 24, 1469–1479 (2013).

    PubMed  PubMed Central  Google Scholar 

  76. Lue, N. F. & Li, Z. Modeling and structure function analysis of the putative anchor site of yeast telomerase. Nucleic Acids Res. 35, 5213–5222 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Wyatt, H. D., Tsang, A. R., Lobb, D. A. & Beattie, T. L. Human telomerase reverse transcriptase (hTERT) Q169 is essential for telomerase function in vitro and in vivo. PLoS ONE 4, e7176 (2009).

    PubMed  PubMed Central  Google Scholar 

  78. Meier, B. et al. trt-1 is the Caenorhabditis elegans catalytic subunit of telomerase. PLoS Genet. 2, e18 (2006).

    PubMed  PubMed Central  Google Scholar 

  79. Osanai, M., Kojima, K. K., Futahashi, R., Yaguchi, S. & Fujiwara, H. Identification and characterization of the telomerase reverse transcriptase of Bombyx mori (silkworm) and Tribolium castaneum (flour beetle). Gene 376, 281–289 (2006).

    CAS  PubMed  Google Scholar 

  80. Akiyama, B. M., Parks, J. W. & Stone, M. D. The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA–DNA hybrids. Nucleic Acids Res. 43, 5537–5549 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lue, N. F. A physical and functional constituent of telomerase anchor site. J. Biol. Chem. 280, 26586–26591 (2005).

    CAS  PubMed  Google Scholar 

  82. Robart, A. R. & Collins, K. Human telomerase domain interactions capture DNA for TEN domain-dependent processive elongation. Mol. Cell 42, 308–318 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Patrick, E. M., Slivka, J. D., Payne, B., Comstock, M. J. & Schmidt, J. C. Observation of processive telomerase catalysis using high-resolution optical tweezers. Nat. Chem. Biol. 16, 801–809 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Jansson, L. I. et al. Telomere DNA G-quadruplex folding within actively extending human telomerase. Proc. Natl Acad. Sci. USA 116, 9350–9359 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Finger, S. N. & Bryan, T. M. Multiple DNA-binding sites in Tetrahymena telomerase. Nucleic Acids Res. 36, 1260–1272 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Sealey, D. C. et al. The N-terminus of hTERT contains a DNA-binding domain and is required for telomerase activity and cellular immortalization. Nucleic Acids Res. 38, 2019–2035 (2010).

    CAS  PubMed  Google Scholar 

  87. Shastry, S., Steinberg-Neifach, O., Lue, N. & Stone, M. D. Direct observation of nucleic acid binding dynamics by the telomerase essential N-terminal domain. Nucleic Acids Res. 46, 3088–3102 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Xia, J., Peng, Y., Mian, I. S. & Lue, N. F. Identification of functionally important domains in the N-terminal region of telomerase reverse transcriptase. Mol. Cell. Biol. 20, 5196–5207 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yen, W. F., Chico, L., Lei, M. & Lue, N. F. Telomerase regulatory subunit Est3 in two Candida species physically interacts with the TEN domain of TERT and telomeric DNA. Proc. Natl Acad. Sci. USA 108, 20370–20375 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Wu, R. A., Tam, J. & Collins, K. DNA-binding determinants and cellular thresholds for human telomerase repeat addition processivity. EMBO J. 36, 1908–1927 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Upton, H. E., Hong, K. & Collins, K. Direct single-stranded DNA binding by Teb1 mediates the recruitment of Tetrahymena thermophila telomerase to telomeres. Mol. Cell. Biol. 34, 4200–4212 (2014).

    PubMed  PubMed Central  Google Scholar 

  92. Zeng, Z. et al. Structural basis for Tetrahymena telomerase processivity factor Teb1 binding to single-stranded telomeric-repeat DNA. Proc. Natl Acad. Sci. USA 108, 20357–20361 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Petrova, O. A. et al. Structure and function of the N-terminal domain of the yeast telomerase reverse transcriptase. Nucleic Acids Res. 46, 1525–1540 (2018).

    CAS  PubMed  Google Scholar 

  94. Zhai, L. T. et al. Crystal structures of N-terminally truncated telomerase reverse transcriptase from fungi. Nucleic Acids Res. 49, 4768–4781 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Wu, R. A. & Collins, K. Human telomerase specialization for repeat synthesis by unique handling of primer–template duplex. EMBO J. 33, 921–935 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Huard, S., Moriarty, T. J. & Autexier, C. The C terminus of the human telomerase reverse transcriptase is a determinant of enzyme processivity. Nucleic Acids Res. 31, 4059–4070 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Qi, X. et al. RNA/DNA hybrid binding affinity determines telomerase template-translocation efficiency. EMBO J. 31, 150–161 (2011).

    PubMed  PubMed Central  Google Scholar 

  98. Nowak, E. et al. Ty3 reverse transcriptase complexed with an RNA–DNA hybrid shows structural and functional asymmetry. Nat. Struct. Mol. Biol. 21, 389–396 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Yang, W. & Lee, Y. S. A DNA-hairpin model for repeat-addition processivity in telomere synthesis. Nat. Struct. Mol. Biol. 22, 844–847 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Lue, N. F. & Peng, Y. Identification and characterization of a telomerase activity from Schizosaccharomyces pombe. Nucleic Acids Res. 25, 4331–4337 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Soudet, J., Jolivet, P. & Teixeira, M. T. Elucidation of the DNA end-replication problem in Saccharomyces cerevisiae. Mol. Cell 53, 954–964 (2014).

    CAS  PubMed  Google Scholar 

  102. Gunisova, S. et al. Identification and comparative analysis of telomerase RNAs from Candida species reveal conservation of functional elements. RNA 15, 546–559 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Forstemann, K. & Lingner, J. Telomerase limits the extent of base pairing between template RNA and telomeric DNA. EMBO Rep. 6, 361–366 (2005).

    PubMed  PubMed Central  Google Scholar 

  104. Zhang, Y. et al. Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. Proc. Natl Acad. Sci. USA 110, 5457–5462 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Taggart, A. K., Teng, S. C. & Zakian, V. A. Est1p as a cell cycle-regulated activator of telomere-bound telomerase. Science 297, 1023–1026 (2002).

    CAS  PubMed  Google Scholar 

  106. Wu, Y. & Zakian, V. A. The telomeric Cdc13 protein interacts directly with the telomerase subunit Est1 to bring it to telomeric DNA ends in vitro. Proc. Natl Acad. Sci. USA 108, 20362–20369 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Tucey, T. M. & Lundblad, V. Regulated assembly and disassembly of the yeast telomerase quaternary complex. Genes Dev. 28, 2077–2089 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hsu, M., Yu, E. Y., Singh, S. M. & Lue, N. F. Mutual dependence of Candida albicans Est1p and Est3p in telomerase assembly and activation. Eukaryot. Cell 6, 1330–1338 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Pennock, E., Buckley, K. & Lundblad, V. Cdc13 delivers separate complexes to the telomere for end protection and replication. Cell 104, 387–396 (2001).

    CAS  PubMed  Google Scholar 

  110. Padmanaban, S., Tesmer, V. M. & Nandakumar, J. Interaction hub critical for telomerase recruitment and primer–template handling for catalysis. Life Sci. Alliance 6, e202201727 (2023).

    CAS  Google Scholar 

  111. Sandhu, R., Sharma, M., Wei, D. & Xu, L. The structurally conserved TELR region on shelterin protein TPP1 is essential for telomerase processivity but not recruitment. Proc. Natl Acad. Sci. USA 118, e2024889118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Rao, T. et al. Structure of Est3 reveals a bimodal surface with differential roles in telomere replication. Proc. Natl Acad. Sci. USA 111, 214–218 (2014).

    CAS  PubMed  Google Scholar 

  113. Frank, A. K. et al. The shelterin TIN2 subunit mediates recruitment of telomerase to telomeres. PLoS Genet. 11, e1005410 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. Pike, A. M., Strong, M. A., Ouyang, J. P. T. & Greider, C. W. TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. Mol. Cell. Biol. 39, e00593-18 (2019).

    PubMed  PubMed Central  Google Scholar 

  115. Savage, S. A. et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82, 501–509 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Zaug, A. J., Goodrich, K. J., Song, J. J., Sullivan, A. E. & Cech, T. R. Reconstitution of a telomeric replicon organized by CST. Nature 608, 819–825 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Cai, S. W. et al. Cryo-EM structure of the human CST-Polα/primase complex in a recruitment state. Nat. Struct. Mol. Biol. 29, 813–819 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. He, Q. et al. Structures of the human CST-Polα–primase complex bound to telomere templates. Nature 608, 826–832 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. He, Y. et al. Structure of Tetrahymena telomerase-bound CST with polymerase α–primase. Nature 608, 813–818 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We apologize to our colleagues whose works are not cited due to space constraints. We thank J. Feigon and K. Nguyen for insightful comments on the manuscript, and we thank A. Young for discussion and helpful suggestions. Work in our laboratories is supported by the Canadian Institutes of Health Research (grant PJT-166130) and a Natural Sciences and Engineering Research Council of Canada Discovery grant (C.A.) and by NSF MCB-1817331, NIH GM107287 and Hearst Endowed Faculty Fellow Fund (N.F.L.).

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  1. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA

    Neal F. Lue

  2. Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Anatomy and Cell Biology and Department of Medicine, McGill University, Montreal, Quebec, Canada

    Chantal Autexier

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Lue, N.F., Autexier, C. Orchestrating nucleic acid–protein interactions at chromosome ends: telomerase mechanisms come into focus. Nat Struct Mol Biol 30, 878–890 (2023). https://doi.org/10.1038/s41594-023-01022-7

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