The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres

1. Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42 : 301–334. doi: 10.1146/annurev.genet.41.110306.130350 18680434

2. Broccoli D, Smogorzewska A, Chong L, de Lange T (1997) Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat Genet 17 : 231–235. 9326950

3. Baumann P, Cech TR (2001) Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292 : 1171–1175. 11349150

4. Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P, et al. (2007) The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445 : 506–510. 17237768

5. Guo X, Deng Y, Lin Y, Cosme-Blanco W, Chan S, et al. (2007) Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J 26 : 4709–4719. 17948054

6. Denchi EL, de Lange T (2007) Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448 : 1068–1071. 17687332

7. Hockemeyer D, Palm W, Else T, Daniels JP, Takai KK, et al. (2007) Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nat Struct Mol Biol 14 : 754–761. 17632522

8. Kim SH, Kaminker P, Campisi J (1999) TIN2, a new regulator of telomere length in human cells. Nat Genet 23 : 405–412. 10581025

9. Ye JZ, Donigian JR, van Overbeek M, Loayza D, Luo Y, et al. (2004) TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem 279 : 47264–47271. 15316005

10. Houghtaling BR, Cuttonaro L, Chang W, Smith S (2004) A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol 14 : 1621–1631. 15380063

11. Kim SH, Davalos AR, Heo SJ, Rodier F, Zou Y, et al. (2008) Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes. J Cell Biol 181 : 447–460. doi: 10.1083/jcb.200710028 18443218

12. Takai KK, Kibe T, Donigian JR, Frescas D, de Lange T (2011) Telomere protection by TPP1/POT1 requires tethering to TIN2. Mol Cell 44 : 647–659. doi: 10.1016/j.molcel.2011.08.043 22099311

13. Kim SH, Beausejour C, Davalos AR, Kaminker P, Heo SJ, et al. (2004) TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem 279 : 43799–43804. 15292264

14. Frescas D, de Lange T (2014) TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1. Mol Cell Biol 34 : 1349–1362. doi: 10.1128/MCB.01052-13 24469404

15. Zhong FL, Batista LF, Freund A, Pech MF, Venteicher AS, et al. (2012) TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 150 : 481–494. doi: 10.1016/j.cell.2012.07.012 22863003

16. Sexton AN, Youmans DT, Collins K (2012) Specificity requirements for human telomere protein interaction with telomerase holoenzyme. J Biol Chem 287 : 34455–34464. doi: 10.1074/jbc.M112.394767 22893708

17. Xin H, Liu D, Wan M, Safari A, Kim H, et al. (2007) TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 445 : 559–562. 17237767

18. Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, et al. (2012) The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492 : 285–289. doi: 10.1038/nature11648 23103865

19. Abreu E, Aritonovska E, Reichenbach P, Cristofari G, Culp B, et al. (2010) TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol Cell Biol 30 : 2971–2982. doi: 10.1128/MCB.00240-10 20404094

20. Zaug AJ, Podell ER, Nandakumar J, Cech TR (2010) Functional interaction between telomere protein TPP1 and telomerase. Genes Dev 24 : 613–622. doi: 10.1101/gad.1881810 20231318

21. Sexton AN, Regalado SG, Lai CS, Cost GJ, O'Neil CM, 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 : 1885–1899. doi: 10.1101/gad.246819.114 25128433

22. Canudas S, Houghtaling BR, Bhanot M, Sasa G, Savage SA, et al. (2011) A role for heterochromatin protein 1gamma at human telomeres. Genes Dev 25 : 1807–1819. doi: 10.1101/gad.17325211 21865325

23. Calado RT, Young NS (2009) Telomere diseases. N Engl J Med 361 : 2353–2365. doi: 10.1056/NEJMra0903373 20007561

24. Armanios M, Blackburn EH (2012) The telomere syndromes. Nat Rev Genet 13 : 693–704. doi: 10.1038/nrg3246 22965356

25. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402 : 551–555. 10591218

26. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, et al. (2001) The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413 : 432–435. 11574891

27. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, et al. (2005) Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 102 : 15960–15964. 16247010

28. Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, et al. (2007) Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 16 : 1619–1629. 17507419

29. Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, et al. (2008) Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A 105 : 8073–8078. doi: 10.1073/pnas.0800042105 18523010

30. Zhong F, Savage SA, Shkreli M, Giri N, Jessop L, et al. (2011) Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev 25 : 11–16. doi: 10.1101/gad.2006411 21205863

31. Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I (2008) 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. doi: 10.1182/blood-2008-05-153445 18669893

32. Walne AJ, Bhagat T, Kirwan M, Gitiaux C, Desguerre I, et al. (2013) Mutations in the telomere capping complex in bone marrow failure and related syndromes. Haematologica 98 : 334–338. doi: 10.3324/haematol.2012.071068 22899577

33. Keller RB, Gagne KE, Usmani GN, Asdourian GK, Williams DA, et al. (2012) CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer 59 : 311–314. doi: 10.1002/pbc.24193 22532422

34. Ballew BJ, Joseph V, De S, Sarek G, Vannier JB, et al. (2013) A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet 9: e1003695. doi: 10.1371/journal.pgen.1003695 24009516

35. Deng Z, Glousker G, Molczan A, Fox AJ, Lamm N, et al. (2013) Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome. Proc Natl Acad Sci U S A 110: E3408–3416. doi: 10.1073/pnas.1300600110 23959892

36. Le Guen T, Jullien L, Touzot F, Schertzer M, Gaillard L, et al. (2013) Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability. Hum Mol Genet 22 : 3239–3249. doi: 10.1093/hmg/ddt178 23591994

37. Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, et al. (2008) TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 82 : 501–509. doi: 10.1016/j.ajhg.2007.10.004 18252230

38. Kocak H, Ballew BJ, Bisht K, Eggebeen R, Hicks BD, et al. (2014) Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev 28 : 2090–2102. doi: 10.1101/gad.248567.114 25233904

39. Chen Y, Yang Y, van Overbeek M, Donigian JR, Baciu P, et al. (2008) A shared docking motif in TRF1 and TRF2 used for differential recruitment of telomeric proteins. Science 319 : 1092–1096. doi: 10.1126/science.1151804 18202258

40. Yang D, He Q, Kim H, Ma W, Songyang Z (2011) TIN2 protein dyskeratosis congenita missense mutants are defective in association with telomerase. J Biol Chem 286 : 23022–23030. doi: 10.1074/jbc.M111.225870 21536674

41. Frescas D, de Lange T (2014) A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice. Genes Dev 28 : 153–166. doi: 10.1101/gad.233395.113 24449270

42. Hendrickson EA (2008) Gene targeting in human somatic cells. In: Conn PM, editor. Source Book of Models for Biomedical Research: Humana Press. pp. 509–525.

43. Bhakta MS, Henry IM, Ousterout DG, Das KT, Lockwood SH, et al. (2013) Highly active zinc-finger nucleases by extended modular assembly. Genome Res 23 : 530–538. doi: 10.1101/gr.143693.112 23222846

44. Ye JZ, de Lange T (2004) TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 36 : 618–623. 15133513

45. Sasa GS, Ribes-Zamora A, Nelson ND, Bertuch AA (2012) Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. Clin Genet 81 : 470–478. doi: 10.1111/j.1399-0004.2011.01658.x 21477109

46. Takai KK, Hooper S, Blackwood S, Gandhi R, de Lange T (2010) In vivo stoichiometry of shelterin components. J Biol Chem 285 : 1457–1467. doi: 10.1074/jbc.M109.038026 19864690

47. Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, et al. (1999) Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5 : 1164–1170. 10502820

48. Diolaiti ME, Cimini BA, Kageyama R, Charles FA, Stohr BA (2013) In situ visualization of telomere elongation patterns in human cells. Nucleic Acids Res.

49. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, et al. (1995) The RNA component of human telomerase. Science 269 : 1236–1241. 7544491

50. Li S, Rosenberg JE, Donjacour AA, Botchkina IL, Hom YK, et al. (2004) Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Cancer Res 64 : 4833–4840. 15256453

51. Marusic L, Anton M, Tidy A, Wang P, Villeponteau B, et al. (1997) Reprogramming of telomerase by expression of mutant telomerase RNA template in human cells leads to altered telomeres that correlate with reduced cell viability. Mol Cell Biol 17 : 6394–6401. 9343401

52. Yi X, Tesmer VM, Savre-Train I, Shay JW, Wright WE (1999) Both transcriptional and posttranscriptional mechanisms regulate human telomerase template RNA levels. Mol Cell Biol 19 : 3989–3997. 10330139

53. Batista LF, Pech MF, Zhong FL, Nguyen HN, Xie KT, et al. (2011) Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474 : 399–402. doi: 10.1038/nature10084 21602826

54. 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. 16339074

55. Femino AM, Fay FS, Fogarty K, Singer RH (1998) Visualization of single RNA transcripts in situ. Science 280 : 585–590. 9554849

56. Agarwal S, Loh YH, McLoughlin EM, Huang J, Park IH, et al. (2010) Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464 : 292–296. doi: 10.1038/nature08792 20164838

57. Lansdorp PM, Verwoerd NP, van de Rijke FM, Dragowska V, Little MT, et al. (1996) Heterogeneity in telomere length of human chromosomes. Hum Mol Genet 5 : 685–691. 8733138

58. Abreu E, Terns RM, Terns MP (2011) Visualization of human telomerase localization by fluorescence microscopy techniques. Methods Mol Biol 735 : 125–137. doi: 10.1007/978-1-61779-092-8_12 21461817

59. Kim NW, Wu F (1997) Advances in quantification and characterization of telomerase activity by the telomeric repeat amplification protocol (TRAP). Nucleic Acids Res 25 : 2595–2597. 9185569