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Control of telomerase action at human telomeres

Abstract

Recent progress has greatly increased the understanding of telomere-bound shelterin proteins and the telomerase holoenzyme, predominantly as separate complexes. Pioneering studies have begun to investigate the requirements for shelterin-telomerase interaction. From this vantage point, focusing on human cells, we review and discuss models for how telomerase and shelterin subunits coordinate to achieve balanced telomere-length homeostasis.

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Figure 1: Human shelterin and telomerase-subunit interactions.

References

  1. Doksani, Y. & de Lange, T. The role of double-strand break repair pathways at functional and dysfunctional telomeres. Cold Spring Harb. Perspect. Biol. 6, a016576 (2014).

    PubMed  PubMed Central  Google Scholar 

  2. Wang, F. et al. The POT1–TPP1 telomere complex is a telomerase processivity factor. Nature 445, 506–510 (2007).This paper reports the structure of the TPP1 OB-fold domain and introduces the idea of TPP1–POT1 stimulation of telomerase activity.

    CAS  PubMed  Google Scholar 

  3. Xin, H. et al. TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. Nature 445, 559–562 (2007).

    CAS  PubMed  Google Scholar 

  4. Abreu, E. et al. TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol. Cell. Biol. 30, 2971–2982 (2010).This work thoroughly investigates the shelterin requirements for telomerase recruitment to telomeres.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Aubert, G. Telomere dynamics and aging. Prog. Mol. Biol. Transl. Sci. 125, 89–111 (2014).

    CAS  PubMed  Google Scholar 

  6. Holohan, B., Wright, W.E. & Shay, J.W. Telomeropathies: an emerging spectrum disorder. J. Cell Biol. 205, 289–299 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Shay, J.W. & Wright, W.E. Role of telomeres and telomerase in cancer. Semin. Cancer Biol. 21, 349–353 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Stewart, J.A., Chaiken, M.F., Wang, F. & Price, C.M. Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation. Mutat. Res. 730, 12–19 (2012).

    CAS  PubMed  Google Scholar 

  9. Griffith, J.D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999).

    CAS  PubMed  Google Scholar 

  10. Doksani, Y., Wu, J.Y., de Lange, T. & Zhuang, X. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell 155, 345–356 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kabir, S., Hockemeyer, D. & de Lange, T. TALEN gene knockouts reveal no requirement for the conserved human shelterin protein Rap1 in telomere protection and length regulation. Cell Rep. 9, 1273–1280 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ye, J.Z. et al. TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J. Biol. Chem. 279, 47264–47271 (2004).

    CAS  PubMed  Google Scholar 

  13. Mattern, K.A. et al. Dynamics of protein binding to telomeres in living cells: implications for telomere structure and function. Mol. Cell. Biol. 24, 5587–5594 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Takai, K.K., Hooper, S., Blackwood, S., Gandhi, R. & de Lange, T. In vivo stoichiometry of shelterin components. J. Biol. Chem. 285, 1457–1467 (2010).This paper quantifies total and telomere-bound shelterin proteins and compares their stoichiometry in human cells with different telomere lengths.

    CAS  PubMed  Google Scholar 

  15. Egan, E.D. & Collins, K. Biogenesis of telomerase ribonucleoproteins. RNA 18, 1747–1759 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Podlevsky, J.D. & Chen, J.J. It all comes together at the ends: telomerase structure, function, and biogenesis. Mutat. Res. 730, 3–11 (2012).

    CAS  PubMed  Google Scholar 

  17. 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 

  18. Collins, K. Physiological assembly and activity of human telomerase complexes. Mech. Ageing Dev. 129, 91–98 (2008).

    CAS  PubMed  Google Scholar 

  19. Nandakumar, J. & Cech, T.R. Finding the end: recruitment of telomerase to telomeres. Nat. Rev. Mol. Cell Biol. 14, 69–82 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Darzacq, X. et al. Stepwise RNP assembly at the site of H/ACA RNA transcription in human cells. J. Cell Biol. 173, 207–218 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Egan, E.D. & Collins, K. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. Mol. Cell. Biol. 32, 2428–2439 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kiss, T., Fayet-Lebaron, E. & Jády, B.E. Box H/ACA small ribonucleoproteins. Mol. Cell 37, 597–606 (2010).

    PubMed  Google Scholar 

  23. Richard, P. et al. A common sequence motif determines the Cajal body-specific localization of box H/ACA scaRNAs. EMBO J. 22, 4283–4293 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tycowski, K.T., Shu, M.D., Kukoyi, A. & Steitz, J.A. A conserved WD40 protein binds the Cajal body localization signal of scaRNP particles. Mol. Cell 34, 47–57 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Venteicher, A.S. et al. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323, 644–648 (2009).Refs. 24 and 25 report the discovery of the protein TCAB1 (WDR79) and its association with an RNA motif for RNP CB localization.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Weinrich, S.L. et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat. Genet. 17, 498–502 (1997).

    CAS  PubMed  Google Scholar 

  27. Mitchell, J.R. & Collins, K. Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase in vivo and in vitro. Mol. Cell 6, 361–371 (2000).

    CAS  PubMed  Google Scholar 

  28. Chen, J.L., Opperman, K.K. & Greider, C.W. A critical stem-loop structure in the CR4–CR5 domain of mammalian telomerase RNA. Nucleic Acids Res. 30, 592–597 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang, Q., Kim, N.K. & Feigon, J. Architecture of human telomerase RNA. Proc. Natl. Acad. Sci. USA 108, 20325–20332 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Tomlinson, R.L., Ziegler, T.D., Supakorndej, T., Terns, R.M. & Terns, M.P. Cell cycle-regulated trafficking of human telomerase to telomeres. Mol. Biol. Cell 17, 955–965 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, J.H. et al. Catalytically active telomerase holoenzyme is assembled in the dense fibrillar component of the nucleolus during S phase. Histochem. Cell Biol. 141, 137–152 (2014).

    CAS  PubMed  Google Scholar 

  32. Hug, N. & Lingner, J. Telomere length homeostasis. Chromosoma 115, 413–425 (2006).

    CAS  PubMed  Google Scholar 

  33. Jády, B.E., Richard, P., Bertrand, E. & Kiss, T. Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres. Mol. Biol. Cell 17, 944–954 (2006).

    PubMed  PubMed Central  Google Scholar 

  34. Blackburn, E.H., Greider, C.W. & Szostak, J.W. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat. Med. 12, 1133–1138 (2006).

    CAS  PubMed  Google Scholar 

  35. Britt-Compton, B. et al. Structural stability and chromosome-specific telomere length is governed by cis-acting determinants in humans. Hum. Mol. Genet. 15, 725–733 (2006).

    CAS  PubMed  Google Scholar 

  36. Cristofari, G. & Lingner, J. Telomere length homeostasis requires that telomerase levels are limiting. EMBO J. 25, 565–574 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Greider, C.W. Telomerase RNA levels limit the telomere length equilibrium. Cold Spring Harb. Symp. Quant. Biol. 71, 225–229 (2006).

    CAS  PubMed  Google Scholar 

  38. Armanios, M. & Blackburn, E.H. The telomere syndromes. Nat. Rev. Genet. 13, 693–704 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chiba, K. et al. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife 4, e07918 (2015).

    PubMed Central  Google Scholar 

  40. Fu, D. & Collins, K. Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation. Mol. Cell 28, 773–785 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Holt, S.E., Aisner, D.L., Shay, J.W. & Wright, W.E. Lack of cell cycle regulation of telomerase activity in human cells. Proc. Natl. Acad. Sci. USA 94, 10687–10692 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vogan, J.M. & Collins, K. Dynamics of human telomerase holoenzyme assembly and subunit exchange across the cell cycle. J. Biol. Chem. 290, 21320–21335 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Stern, J.L., Zyner, K.G., Pickett, H.A., Cohen, S.B. & Bryan, T.M. Telomerase recruitment requires both TCAB1 and Cajal bodies independently. Mol. Cell. Biol. 32, 2384–2395 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhong, F. et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25, 11–16 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Jády, B.E., Bertrand, E. & Kiss, T. Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body-specific localization signal. J. Cell Biol. 164, 647–652 (2004).

    PubMed  PubMed Central  Google Scholar 

  46. Tomlinson, R.L., Li, J., Culp, B.R., Terns, R.M. & Terns, M.P. A Cajal body-independent pathway for telomerase trafficking in mice. Exp. Cell Res. 316, 2797–2809 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Cusanelli, E., Romero, C.A. & Chartrand, P. Telomeric noncoding RNA TERRA is induced by telomere shortening to nucleate telomerase molecules at short telomeres. Mol. Cell 51, 780–791 (2013).

    CAS  PubMed  Google Scholar 

  48. Chen, Y. et al. Human cells lacking coilin and Cajal bodies are proficient in telomerase assembly, trafficking and telomere maintenance. Nucleic Acids Res. 43, 385–395 (2015).This study reveals a surprising lack of change in telomere maintenance in cancer cells with complete elimination of coilin, as accomplished by gene disruption.

    CAS  PubMed  Google Scholar 

  49. Cristofari, G. et al. Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation. Mol. Cell 27, 882–889 (2007).

    CAS  PubMed  Google Scholar 

  50. Smogorzewska, A. & de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004).

    CAS  PubMed  Google Scholar 

  51. van Steensel, B. & de Lange, T. Control of telomere length by the human telomeric protein TRF1. Nature 385, 740–743 (1997).This paper is the initial study that demonstrated control of telomere length by a telomeric DNA–binding protein, in cancer cells.

    CAS  PubMed  Google Scholar 

  52. Smogorzewska, A. et al. Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol. 20, 1659–1668 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ancelin, K. et al. Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol. Cell. Biol. 22, 3474–3487 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Loayza, D. & De Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013–1018 (2003).

    CAS  PubMed  Google Scholar 

  55. Schoeftner, S. & Blasco, M.A. Chromatin regulation and non-coding RNAs at mammalian telomeres. Semin. Cell Dev. Biol. 21, 186–193 (2010).

    CAS  PubMed  Google Scholar 

  56. Canudas, S. et al. A role for heterochromatin protein 1γ at human telomeres. Genes Dev. 25, 1807–1819 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 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 

  58. 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 

  59. 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 

  60. Sexton, A.N. et al. Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes Dev. 28, 1885–1899 (2014).This work, through genome editing, investigates the functions of TPP1 in human pluripotent stem cells and uncovers a multiplicity of TPP1 requirements for telomerase recruitment and activation.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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 Central  Google Scholar 

  62. Nakashima, M., Nandakumar, J., Sullivan, K.D., Espinosa, J.M. & Cech, T.R. Inhibition of telomerase recruitment and cancer cell death. J. Biol. Chem. 288, 33171–33180 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hwang, H., Buncher, N., Opresko, P.L. & Myong, S. POT1–TPP1 regulates telomeric overhang structural dynamics. Structure 20, 1872–1880 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lei, M., Zaug, A.J., Podell, E.R. & Cech, T.R. Switching human telomerase on and off with hPOT1 protein in vitro. J. Biol. Chem. 280, 20449–20456 (2005).

    CAS  PubMed  Google Scholar 

  65. Zaug, A.J., Podell, E.R. & Cech, T.R. Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proc. Natl. Acad. Sci. USA 102, 10864–10869 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kelleher, C., Kurth, I. & Lingner, J. Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol. Cell. Biol. 25, 808–818 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Churikov, D. & Price, C.M. Pot1 and cell cycle progression cooperate in telomere length regulation. Nat. Struct. Mol. Biol. 15, 79–84 (2008).

    CAS  PubMed  Google Scholar 

  68. Ye, J.Z. et al. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 18, 1649–1654 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Rai, R. et al. The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection. Nat. Struct. Mol. Biol. 18, 1400–1407 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zemp, I. & Lingner, J. The shelterin component TPP1 is a binding partner and substrate for the deubiquitinating enzyme USP7. J. Biol. Chem. 289, 28595–28606 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 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 

  72. Walne, A.J., Vulliamy, T., Beswick, R., Kirwan, M. & Dokal, I. TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 112, 3594–3600 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Frescas, D. & de Lange, T.A. TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice. Genes Dev. 28, 153–166 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Yang, D., He, Q., Kim, H., Ma, W. & Songyang, Z. TIN2 protein dyskeratosis congenita missense mutants are defective in association with telomerase. J. Biol. Chem. 286, 23022–23030 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Price, C.M. et al. Evolution of CST function in telomere maintenance. Cell Cycle 9, 3157–3165 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Casteel, D.E. et al. A DNA polymerase-αprimase cofactor with homology to replication protein A-32 regulates DNA replication in mammalian cells. J. Biol. Chem. 284, 5807–5818 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lue, N.F., Chan, J., Wright, W.E. & Hurwitz, J. The CDC13-STN1-TEN1 complex stimulates Pol α activity by promoting RNA priming and primase-to-polymerase switch. Nat. Commun. 5, 5762 (2014).

    CAS  PubMed  Google Scholar 

  78. Chen, L.Y., Redon, S. & Lingner, J. The human CST complex is a terminator of telomerase activity. Nature 488, 540–544 (2012).

    CAS  PubMed  Google Scholar 

  79. Wu, P., Takai, H. & de Lange, T. Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150, 39–52 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lenain, C. et al. The Apollo 5′ exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr. Biol. 16, 1303–1310 (2006).

    CAS  PubMed  Google Scholar 

  81. van Overbeek, M. & de Lange, T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr. Biol. 16, 1295–1302 (2006).

    CAS  PubMed  Google Scholar 

  82. Touzot, F. et al. Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome. Proc. Natl. Acad. Sci. USA 107, 10097–10102 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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 

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Acknowledgements

We thank A. Wu and J. Boyle for comments and the US National Institutes of Health (RCA196884A (D.H.) and HL0795985 (K.C.)) for funding.

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Correspondence to Dirk Hockemeyer or Kathleen Collins.

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Hockemeyer, D., Collins, K. Control of telomerase action at human telomeres. Nat Struct Mol Biol 22, 848–852 (2015). https://doi.org/10.1038/nsmb.3083

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