Chromosoma

, Volume 115, Issue 6, pp 413–425 | Cite as

Telomere length homeostasis

Review

Abstract

The physical ends of chromosomes, known as telomeres, protect chromosome ends from nucleolytic degradation and DNA repair activities. Conventional DNA replication enzymes lack the ability to fully replicate telomere ends. In addition, nucleolytic activities contribute to telomere erosion. Short telomeres trigger DNA damage checkpoints, which mediate cellular senescence. Telomere length homeostasis requires telomerase, a cellular reverse transcriptase, which uses an internal RNA moiety as a template for the synthesis of telomere repeats. Telomerase elongates the 3′ ends of chromosomes, whereas the complementary strand is filled in by conventional DNA polymerases. In humans, telomerase is ubiquitously expressed only during the first weeks of embryogenesis, and is subsequently downregulated in most cell types. Correct telomere length setting is crucial for long-term survival. The telomere length reserve must be sufficient to avoid premature cellular senescence and the acceleration of age-related disease. On the other side, telomere shortening suppresses tumor formation through limiting the replicative potential of cells. In recent years, novel insight into the regulation of telomerase at chromosome ends has increased our understanding on how telomere length homeostasis in telomerase-positive cells is achieved. Factors that recruit telomerase to telomeres in a cell cycle-dependent manner have been identified in Saccharomyces cerevisiae. In humans, telomerase assembles with telomeres during S phase of the cell cycle. Presumably through mediating formation of alternative telomere structures, telomere-binding proteins regulate telomerase activity in cis to favor preferential elongation of the shortest telomeres. Phosphoinositide 3-kinase related kinases are also required for telomerase activation at chromosome ends, at least in budding and fission yeast. In vivo analysis of telomere elongation kinetics shows that telomerase does not act on every telomere in each cell cycle but that it exhibits an increasing preference for telomeres as their lengths decline. This suggests a model in which telomeres switch between extendible and nonextendible states in a length-dependent manner. In this review we expand this model to incorporate the finding that telomerase levels also limit telomere length and we propose a second switch between a non-telomerase-associated “extendible” and a telomerase-associated “extending” state.

References

  1. Adams AK, Holm C (1996) Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae. Mol Cell Biol 16:4614–4620PubMedGoogle Scholar
  2. Ancelin K, Brunori M, Bauwens S, Koering CE, Brun C, Ricoul M, Pommier JP, Sabatier L, Gilson E (2002) 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 22:3474–3487PubMedCrossRefGoogle Scholar
  3. 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 24:3552–3561PubMedCrossRefGoogle Scholar
  4. Azzalin CM, Redon S, Lingner J (2005) S. cerevisiae Est1/H. sapiens SMG6 protein family members function in telomere metabolism. In: Maquat LE (ed) Nonsense-mediated mRNA decay. Landes Bioscience, Georgetown, http://eurekah.com/abstract.php?cha pid=2781&bookid=210&catid=54
  5. Baumann P, Cech T (2001) Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292:1171–1175PubMedCrossRefGoogle Scholar
  6. Berthiau AS, Yankulov K, Bah A, Revardel E, Luciano P, Wellinger RJ, Geli V, Gilson E (2006) Subtelomeric proteins negatively regulate telomere elongation in budding yeast. EMBO J 25:846–856PubMedCrossRefGoogle Scholar
  7. Bianchi A, Smith S, Chong L, Elias P, de Lange T (1997) TRF1 is a dimer and bends telomeric DNA. EMBO J 16:1785–1794PubMedCrossRefGoogle Scholar
  8. Bianchi A, Negrini S, Shore D (2004) Delivery of yeast telomerase to a DNA break depends on the recruitment functions of Cdc13 and Est1. Mol Cell 16:139–146PubMedCrossRefGoogle Scholar
  9. Boule JB, Vega LR, Zakian VA (2005) The yeast Pif1p helicase removes telomerase from telomeric DNA. Nature 438:57–61PubMedCrossRefGoogle Scholar
  10. Boulton SJ, Jackson SP (1998) Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J 17:1819–1828PubMedCrossRefGoogle Scholar
  11. Bourns BD, Alexander MK, Smith AM, Zakian VA (1998) Sir proteins, Rif proteins, and Cdc13p bind Saccharromyces telomers in vivo. Mol Cell Biol 18:5600–5608PubMedGoogle Scholar
  12. Budd ME, Reis CC, Smith S, Myung K, Campbell JL (2006) Evidence suggesting that Pif1 helicase functions in DNA replication with the Dna2 helicase/nuclease and DNA polymerase delta. Mol Cell Biol 26:2490–2500PubMedCrossRefGoogle Scholar
  13. Chai W, Du Q, Shay JW, Wright WE (2006a) Human telomeres have different overhang sizes at leading versus lagging strands. Mol Cell 21:427–435PubMedCrossRefGoogle Scholar
  14. Chai W, Sfeir AJ, Hoshiyama H, Shay JW, Wright WE (2006b) The involvement of the Mre11/Rad50/Nbs1 complex in the generation of G-overhangs at human telomeres. EMBO Rep 7:225–230PubMedCrossRefGoogle Scholar
  15. Chandra A, Hughes TR, Nugent CI, Lundblad V (2001) Cdc13 both positively and negatively regulates telomere replication. Genes Dev 15:404–414PubMedCrossRefGoogle Scholar
  16. Chang W, Dynek JN, Smith S (2003) TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev 17:1328–1333PubMedCrossRefGoogle Scholar
  17. Chen J-L, Greider CW (2006) Telomerase biochemistry and biogenesis. In: de Lange T, Lundblad V, Blackburn EH (eds) Telomeres. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 49–79Google Scholar
  18. Chen JL, Blasco MA, Greider CW (2000) Secondary structure of vertebrate telomerase RNA. Cell 100:503–514PubMedCrossRefGoogle Scholar
  19. Colgin LM, Baran K, Baumann P, Cech TR, Reddel RR (2003) Human POT1 facilitates telomere elongation by telomerase. Curr Biol 13:942–946PubMedCrossRefGoogle Scholar
  20. Conrad M, Wright J, Wolf J, Zakian V (1990) RAP1 protein interacts with yeast telomeres in vivo: overproduction alters telomere structure and decreases chromosome stability. Cell 63:739–750PubMedCrossRefGoogle Scholar
  21. Cook BD, Dynek JN, Chang W, Shostak G, Smith S (2002) Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 22:332–342PubMedCrossRefGoogle Scholar
  22. Cristofari G, Lingner J (2006a) The telomerase ribonucleoprotein particle. In: de Lange T, Lundblad V, Blackburn EH (ed) Telomeres. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 21–47Google Scholar
  23. Cristofari G, Lingner J (2006b) Telomere length homeostasis requires that telomerase levels are limiting. EMBO J 25:565–574PubMedCrossRefGoogle Scholar
  24. Dandjinou AT, Levesque N, Larose S, Lucier JF, Elela SA, Wellinger RJ (2004) A phylogenetically based secondary structure for the yeast telomerase RNA. Curr Biol 14:1148–1158PubMedCrossRefGoogle Scholar
  25. de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110PubMedCrossRefGoogle Scholar
  26. Diede SJ, Gottschling DE (1999) Telomerase-mediated telomere addition in vivo requires DNA primase and DNA polymerases alpha and delta. Cell 99:723–733PubMedCrossRefGoogle Scholar
  27. Evans SK, Lundblad V (1999) Est1 and Cdc13 as comediators of telomerase access. Science 286:117–120PubMedCrossRefGoogle Scholar
  28. Fisher TS, Taggart AK, Zakian VA (2004) Cell cycle-dependent regulation of yeast telomerase by Ku. Nat Struct Mol Biol 11:1198–1205PubMedCrossRefGoogle Scholar
  29. Garcia-Cao M, Gonzalo S, Dean D, Blasco MA (2002) A role for the Rb family of proteins in controlling telomere length. Nat Genet 32:415–419PubMedCrossRefGoogle Scholar
  30. Garcia-Cao M, O’Sullivan R, Peters AH, Jenuwein T, Blasco MA (2004) Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 36:94–99PubMedCrossRefGoogle Scholar
  31. Garvik B, Carson M, Hartwell L (1995) Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol Cell Biol 15:6128–6138PubMedGoogle Scholar
  32. Grandin N, Reed SI, Charbonneau M (1997) Stn1, a new Saccharomyces cerevisiae protein, is implicated in telomere size regulation in association with Cdc13. Genes Dev 11:512–527PubMedGoogle Scholar
  33. Grandin N, Damon C, Charbonneau M (2001) Ten1 functions in telomere end protection and length regulation in association with Stn1 and Cdc13. EMBO J 20:1173–1183PubMedCrossRefGoogle Scholar
  34. Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43:405–413PubMedCrossRefGoogle Scholar
  35. Greider CW, Blackburn EH (1987) The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 51:887–898PubMedCrossRefGoogle Scholar
  36. Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337:331–337PubMedCrossRefGoogle Scholar
  37. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514PubMedCrossRefGoogle Scholar
  38. Grossi S, Puglisi A, Dmitriev PV, Lopes M, Shore D (2004) Pol12, the B subunit of DNA polymerase alpha, functions in both telomere capping and length regulation. Genes Dev 18:992–1006PubMedCrossRefGoogle Scholar
  39. Hao LY, Armanios M, Strong MA, Karim B, Feldser DM, Huso D, Greider CW (2005) Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123:1121–1131PubMedCrossRefGoogle Scholar
  40. Hardy CF, Sussel L, Shore D (1992) A RAP1-interacting protein involved in transcriptional silencing and telomere length regulation. Genes Dev 6:801–814PubMedGoogle Scholar
  41. Hathcock KS, Hemann MT, Opperman KK, Strong MA, Greider CW, Hodes RJ (2002) Haploinsufficiency of mTR results in defects in telomere elongation. Proc Natl Acad Sci USA 99:3591–3596PubMedCrossRefGoogle Scholar
  42. Hemann MT, Strong MA, Hao LY, Greider CW (2001) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107:67–77PubMedCrossRefGoogle Scholar
  43. Holt SE, Aisner DL, Shay JW, Wright WE (1997) Lack of cell cycle regulation of telomerase activity in human cells. Proc Natl Acad Sci USA 94:10687–10692PubMedCrossRefGoogle Scholar
  44. 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 14:1621–1631PubMedCrossRefGoogle Scholar
  45. Jacob NK, Kirk KE, Price CM (2003) Generation of telomeric G strand overhangs involves both G and C strand cleavage. Mol Cell 11:1021–1032PubMedCrossRefGoogle Scholar
  46. Jady BE, Richard P, Bertrand E, Kiss T (2006) Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres. Mol Biol Cell 17:944–954PubMedCrossRefGoogle Scholar
  47. Kaminker PG, Kim SH, Taylor RD, Zebarjadian Y, Funk WD, Morin GB, Yaswen P, Campisi J (2001) TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression. J Biol Chem 276:35891–35899PubMedCrossRefGoogle Scholar
  48. Kelleher C, Kurth I, Lingner J (2005) Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol Cell Biol 25:808–818PubMedCrossRefGoogle Scholar
  49. Kim SH, Beausejour C, Davalos AR, Kaminker P, Heo SJ, Campisi J (2004) TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem 279:43799–43804PubMedCrossRefGoogle Scholar
  50. Kim SH, Kaminker P, Campisi J (1999) TIN2, a new regulator of telomere length in human cells. Nat Genet 23:405–412PubMedCrossRefGoogle Scholar
  51. Klobutcher LA, Swanton MT, Donini P, Prescott DM (1981) All gene-sized DNA molecules in four species of hypotrichs have the same terminal sequence and an unusual 3′ terminus. Proc Natl Acad Sci USA 78:3015–3019PubMedCrossRefGoogle Scholar
  52. Larrivee M, LeBel C, Wellinger RJ (2004) The generation of proper constitutive G-tails on yeast telomeres is dependent on the MRX complex. Genes Dev 18:1391–1396PubMedCrossRefGoogle Scholar
  53. Lei M, Podell ER, Cech TR (2004) Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat Struct Mol Biol 11:1223–1229PubMedCrossRefGoogle Scholar
  54. Lei M, Zaug AJ, Podell ER, Cech TR (2005) Switching human telomerase on and off with hPOT1 protein in vitro. J Biol Chem 280:20449–20456PubMedCrossRefGoogle Scholar
  55. Lendvay TS, Morris DK, Sah J, Balasubramanian B, Lundblad V (1996) Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics 144:1399–1412PubMedGoogle Scholar
  56. Li B, de Lange T (2003) Rap1 affects the length and heterogeneity of human telomeres. Mol Biol Cell 14:5060–5068PubMedCrossRefGoogle Scholar
  57. Li B, Oestreich S, de Lange T (2000) Identification of human Rap1: implications for telomere evolution. Cell 101:471–483PubMedCrossRefGoogle Scholar
  58. Lingner J, Promisel Cooper J, Cech TR (1995) Telomerase and DNA end replication: no longer a lagging strand problem? Science 269:1533–1534PubMedCrossRefGoogle Scholar
  59. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR (1997) Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276:561–567PubMedCrossRefGoogle Scholar
  60. Liu D, O’Connor MS, Qin J, Songyang Z (2004a) Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 279:51338–51342PubMedCrossRefGoogle Scholar
  61. Liu D, Safari A, O’Connor MS, Chan DW, Laegeler A, Qin J, Songyang Z (2004b) PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol 6:673–680PubMedCrossRefGoogle Scholar
  62. Liu Y, Kha H, Ungrin M, Robinson MO, Harrington L (2002) Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert. Proc Natl Acad Sci USA 99:3597–3602PubMedCrossRefGoogle Scholar
  63. Loayza D, De Lange T (2003) POT1 as a terminal transducer of TRF1 telomere length control. Nature 424:1013–1018CrossRefGoogle Scholar
  64. Lundblad V, Szostak JW (1989) A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57:633–643PubMedCrossRefGoogle Scholar
  65. Lustig A, Kurtz S, Shore D (1990) Involvement of the silencer and UAS binding protein Rap1 in regulation of telomere length. Science 250:549–553PubMedCrossRefGoogle Scholar
  66. Makarov VL, Hirose Y, Langmore JP (1997) Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell 88:657–666PubMedCrossRefGoogle Scholar
  67. Marcand S, Gilson E, Shore D (1997) A protein-counting mechanism for telomere length regulation in yeast. Science 275:986–990PubMedCrossRefGoogle Scholar
  68. Marcand S, Brevet V, Gilson E (1999) Progressive cis-inhibition of telomerase upon telomere elongation. EMBO J 18:3509–3519PubMedCrossRefGoogle Scholar
  69. Marcand S, Brevet V, Mann C, Gilson E (2000) Cell cycle restriction of telomere elongation. Curr Biol 10:487–490PubMedCrossRefGoogle Scholar
  70. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402:551–555PubMedCrossRefGoogle Scholar
  71. Naito T, Matsuura A, Ishikawa F (1998) Circular chromosome formation in a fission yeast mutant defective in two atm homologues. Nat Genet 20:203–206PubMedCrossRefGoogle Scholar
  72. Nakamura M, Nabetani A, Mizuno T, Hanaoka F, Ishikawa F (2005) Alterations of DNA and chromatin structures at telomeres and genetic instability in mouse cells defective in DNA polymerase alpha. Mol Cell Biol 25:11073–11088PubMedCrossRefGoogle Scholar
  73. Nugent CI, Hughes TR, Lue NF, Lundblad V (1996) Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance. Science 274:249–252PubMedCrossRefGoogle Scholar
  74. O’Connor MS, Safari A, Liu D, Qin J, Songyang Z (2004) The human Rap1 protein complex and modulation of telomere length. J Biol Chem 279:28585–28591PubMedCrossRefGoogle Scholar
  75. Olovnikoff AM (1973) A theory of marginotomy. The incomplete copying of template margins in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41:181–190CrossRefGoogle Scholar
  76. Opresko PL, Mason PA, Podell ER, Lei M, Hickson ID, Cech TR, Bohr VA (2005) POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. J Biol Chem 280:32069–32080PubMedCrossRefGoogle Scholar
  77. Ouellette MM, Liao M, Herbert BS, Johnson M, Holt SE, Liss HS, Shay JW, Wright WE (2000) Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J Biol Chem 275:10072–10076PubMedCrossRefGoogle Scholar
  78. Pennock E, Buckley K, Lundblad V (2001) Cdc13 delivers separate complexes to the telomere for end protection and replication. Cell 104:387–396PubMedCrossRefGoogle Scholar
  79. Qi H, Zakian VA (2000) The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase alpha and the telomerase-associated Est1 protein. Genes Dev 14:1777–1788PubMedGoogle Scholar
  80. Reichenbach P, Hoss 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 13:568–574PubMedCrossRefGoogle Scholar
  81. Ritchie KB, Mallory JC, Petes TD (1999) Interactions of TLC1 (which encodes the RNA subunit of telomerase), TEL1, and MEC1 in regulating telomere length in the yeast Saccharomyces cerevisiae. Mol Cell Biol 19:6065–6075PubMedGoogle Scholar
  82. Samper E, Flores JM, Blasco MA (2001) Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep 2:800–807PubMedCrossRefGoogle Scholar
  83. Sbodio JI, Lodish HF, Chi NW (2002) Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase). Biochem J 361:451–459PubMedCrossRefGoogle Scholar
  84. Schramke V, Luciano P, Brevet V, Guillot S, Corda Y, Longhese MP, Gilson E, Geli V (2004) RPA regulates telomerase action by providing Est1p access to chromosome ends. Nat Genet 36:46–54PubMedCrossRefGoogle Scholar
  85. Seimiya H, Smith S (2002) The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182). J Biol Chem 277:14116–14126PubMedCrossRefGoogle Scholar
  86. Seto AG, Zaug AJ, Sobel SG, Wolin SL, Cech TR (1999) Saccharomyces cerevisiae telomerase is an Sm small nuclear ribonucleoprotein particle. Nature 401:177–180PubMedCrossRefGoogle Scholar
  87. Sfeir AJ, Chai W, Shay JW, Wright WE (2005) Telomere-end processing the terminal nucleotides of human chromosomes. Mol Cell 18:131–138PubMedCrossRefGoogle Scholar
  88. Shampay J, Szostak J, Blackburn E (1984) DNA sequences of telomeres maintained in yeast. Nature 310:154–157PubMedCrossRefGoogle Scholar
  89. Smith S, de Lange T (2000) Tankyrase promotes telomere elongation in human cells. Curr Biol 10:1299–1302PubMedCrossRefGoogle Scholar
  90. Smith S, Giriat I, Schmitt A, de Lange T (1998) Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 282:1484–1487PubMedCrossRefGoogle Scholar
  91. Smogorzewska A, De Lange T (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem 73:177–208PubMedCrossRefGoogle Scholar
  92. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T (2000) Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 20:1659–1668PubMedCrossRefGoogle Scholar
  93. 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 13:698–704PubMedCrossRefGoogle Scholar
  94. Stellwagen AE, Haimberger ZW, Veatch JR, Gottschling DE (2003) Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev 17:2384–2395PubMedCrossRefGoogle Scholar
  95. Szostak J, Blackburn E (1982) Cloning yeast telomeres on linear plasmid vectors. Cell 29:245–255PubMedCrossRefGoogle Scholar
  96. Taggart AK, Teng SC, Zakian VA (2002) Est1p as a cell cycle-regulated activator of telomere-bound telomerase. Science 297:1023–1026PubMedCrossRefGoogle Scholar
  97. Takata H, Kanoh Y, Gunge N, Shirahige K, Matsuura A (2004) Reciprocal association of the budding yeast ATM-related proteins Tel1 and Mec1 with telomeres in vivo. Mol Cell 14:515–522PubMedCrossRefGoogle Scholar
  98. Takata H, Tanaka Y, Matsuura A (2005) Late S phase-specific recruitment of Mre11 complex triggers hierarchical assembly of telomere replication proteins in Saccharomyces cerevisiae. Mol Cell 17:573–583PubMedCrossRefGoogle Scholar
  99. Teixeira MT, Arneric M, Sperisen P, Lingner J (2004) Telomere length homeostasis is achieved via a switch between telomerase-extendible and -nonextendible states. Cell 117:323–335PubMedCrossRefGoogle Scholar
  100. Ten Hagen KG, Gilbert DM, Willard HF, Cohen SN (1990) Replication timing of DNA sequences associated with human centromeres and telomeres. Mol Cell Biol 10:6348–6355PubMedGoogle Scholar
  101. Tomlinson RL, Ziegler TD, Supakorndej T, Terns RM, Terns MP (2006) Cell cycle-regulated trafficking of human telomerase to telomeres. Mol Biol Cell 17:955–965PubMedCrossRefGoogle Scholar
  102. van Steensel B, de Lange T (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385:740–743PubMedCrossRefGoogle Scholar
  103. Verdun RE, Crabbe L, Haggblom C, Karlseder J (2005) Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell 20:551–561PubMedCrossRefGoogle Scholar
  104. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I (2001) The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413:432–435PubMedCrossRefGoogle Scholar
  105. Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I (2005) Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis 34:257–263PubMedCrossRefGoogle Scholar
  106. Watson J (1972) Origin of concatemeric T7 DNA. Nat New Biol 239:197–201PubMedCrossRefGoogle Scholar
  107. Wellinger RJ, Wolf AJ, Zakian VA (1993) Saccharomyces telomeres acquire single-strand TG1-3 tails late in S phase. Cell 72:51–60PubMedCrossRefGoogle Scholar
  108. Wotton D, Shore D (1997) Novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Genes Dev 11:748–760PubMedGoogle Scholar
  109. Wright WE, Tesmer VM, Liao ML, Shay JW (1999) Normal human telomeres are not late replicating. Exp Cell Res 251:492–499PubMedCrossRefGoogle Scholar
  110. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS (2005) Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 352:1413–1424PubMedCrossRefGoogle Scholar
  111. Yang Q, Zheng YL, Harris CC (2005) POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 25:1070–1080PubMedCrossRefGoogle Scholar
  112. Ye JZ, de Lange T (2004) TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 36:618–623PubMedCrossRefGoogle Scholar
  113. Ye JZ, Donigian JR, van Overbeek M, Loayza D, Luo Y, Krutchinsky AN, Chait BT, de Lange T (2004a) TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem 279:47264–47271PubMedCrossRefGoogle Scholar
  114. Ye JZ, Hockemeyer D, Krutchinsky AN, Loayza D, Hooper SM, Chait BT, de Lange T (2004b) POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev 18:1649–1654PubMedCrossRefGoogle Scholar
  115. Yu GL, Bradley JD, Attardi LD, Blackburn EH (1990) In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs. Nature 344:126–132PubMedCrossRefGoogle Scholar
  116. Zahler AM, Williamson JR, Cech TR, Prescott DM (1991) Inhibition of telomerase by G-quartet DNA structures. Nature 350:718–720PubMedCrossRefGoogle Scholar
  117. Zappulla DC, Cech TR (2004) Yeast telomerase RNA: a flexible scaffold for protein subunits. Proc Natl Acad Sci USA 101:10024–10029PubMedCrossRefGoogle Scholar
  118. Zaug AJ, Podell ER, Cech TR (2005) Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proc Natl Acad Sci USA 102:10864–10869PubMedCrossRefGoogle Scholar
  119. Zhu LX, Hathcock KS, Hande P, Lansdorp PM, Seldin MF, Hodes RJ (1998) Telomere length regulation in mice is linked to a novel chromosome locus. Proc Natl Acad Sci USA 95:8648–8653PubMedCrossRefGoogle Scholar
  120. Zhu XD, Kuster B, Mann M, Petrini JH, Lange T (2000) Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet 25:347–352PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Swiss Institute for Experimental Cancer Research (ISREC) and National Center of Competence in Research “Frontiers in Genetics”École Polytechnique Fédérale de Lausanne (EPFL)Epalinges s/LausanneSwitzerland

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