Skip to main content
PMC home page
Cytotechnology logoLink to Cytotechnology
. 2004 Jun;45(1-2):3–12. doi: 10.1007/s10616-004-5120-6

Function, replication and structure of the mammalian telomere

Dominique Broccoli 1,✉
PMCID: PMC3449957  PMID: 19003238

Abstract

Telomeres are specialized structures at the ends of linear chromosomes that were originally defined functionally based on observations first by Muller (1938) and subsequently by McClintock (1941) that naturally occurring chromosome ends do not behave as double-stranded DNA breaks, in spite of the fact that they are the physical end of a linear, duplex DNA molecule. Double-stranded DNA breaks are highly unstable entities, being susceptible to nucleolytic attack and giving rise to chromosome rearrangements through end-to-end fusions and recombination events. In contrast, telomeres confer stability upon chromosome termini, as evidenced by the fact that chromosomes are extraordinarily stable through multiple cell divisions and even across evolutionary time. This protective function of telomeres is due to the formation of a nucleoprotein complex that sequesters the end of the DNA molecule, rendering it inaccessible to nucleases and recombinases as well as preventing the telomere from activating the DNA damage checkpoint pathways. The capacity of a functional end-protective complex to form is dependent upon maintenance of sufficient telomeric DNA. We have learned a great deal about telomere structure and how this specialized nucleoprotein complex confers stability on chromosome ends since the original observations that defined telomeres were made. This review summarizes our current understanding of mammalian telomere replication, structure and function.

Keywords: Aging, Cancer, Chromosome stability, Telomerase, Telomere structure

Full Text

The Full Text of this article is available as a PDF (260.3 KB).

Glossary

53BP1

TP53 binding protein 1

ATM

Ataxia telangiectasia mutated

BRCT

BRCA1 carboxy terminal

DAT

Dissociates activities of telomerase

DNA-PKcs

DNA-dependent protein kinase catalytic subunit

EST1/hEST1

Ever shorter telomeres 1

MRN

MRE11/RAD50/NBS1 complex

PARP

Poly ADP-ribose polymerase

PINX1

Pin2/TRF1 interacting protein

POT1

Protection of telomeres 1

RAD54

radiation senstitivity mutant 54

hRAP1

human homologue of S. cerevisiae Repressor Activator Protein 1

hTERT/mTERT

human and mouse homologues of telomerase reverse transcriptase catalytic subunit

hTERTα

alternatively spliced inhibitory form of hTERT

TIN2

TRF1 interacting protein 2

TPE

Telomeric position effect

hTR/mTR

Human and mouse homologues telomerase template RNA subunit

TRF1

TTAGGG-repeat binding factor 1

TRF2

TTAGGG-repeat binding factor 2

XPF-ERCC1

Xeroderma pigmentosum complementation group F/Excision repair cross-complementing 1

XRCC4

X-ray-complementing Chinese hamster gene 4.

References

  1. Armbruster B.N., Banik S.S., Guo C., Smith A.C., Counter C.M. N-terminal domains of the human telomerase catalytic subunit required for enzyme activity in vivo. Mol. Cell Biol. 2001;21:7775–7786. doi: 10.1128/MCB.21.22.7775-7786.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armbruster B.N., Etheridge K.T., Broccoli D., Counter C.M. Putative telomere-recruiting domain in the catalytic subunit of human telomerase. Mol. Cell Biol. 2003;23:3237–3246. doi: 10.1128/MCB.23.9.3237-3246.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armbruster B.N., Linardic C.M., Veldman T., Bansal N.P., Downie D.L., Counter C.M. Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1. Mol. Cell Biol. 2004;24:3552–3561. doi: 10.1128/MCB.24.8.3552-3561.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baumann P., Cech T.R. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science. 2001;292:1171–1175. doi: 10.1126/science.1060036. [DOI] [PubMed] [Google Scholar]
  5. Baur J.A., Zou Y., Shay J.W., Wright W.E. Telomere position effect in human cells. Science. 2001;292:2075–2077. doi: 10.1126/science.1062329. [DOI] [PubMed] [Google Scholar]
  6. Beattie T.L., Zhou W., Robinson M.O., Harrington L. Functional multimerization of the human telomerase reverse transcriptase. Mol. Cell Biol. 2001;21:6151–6160. doi: 10.1128/MCB.21.18.6151-6160.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blasco M.A. Telomeres in cancer and aging: lessons from the mouse. Cancer Lett. 2003;194:183–188. doi: 10.1016/S0304-3835(02)00705-X. [DOI] [PubMed] [Google Scholar]
  8. Blasco M.A. Telomere epigenetics: a higher–order control of telomere length in mammalian cells. Carcinogenesis. 2004;25:1083–1087. doi: 10.1093/carcin/bgh185. [DOI] [PubMed] [Google Scholar]
  9. Broccoli D., Smogorzewska A., Chong L., de Lange T. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat. Genet. 1997;17:231–235. doi: 10.1038/ng1097-231. [DOI] [PubMed] [Google Scholar]
  10. Broccoli D., Young J.W., de Lange T. Telomerase activity in normal and malignant hematopoietic cells. Proc. Natl. Acad. Sci. USA. 1995;92:9082–9086. doi: 10.1073/pnas.92.20.9082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cerone M.A., Londono-Vallejo J.A., Bacchetti S. Telomere maintenance by telomerase and by recombination can coexist in human cells. Hum. Mol. Genet. 2001;10:1945–1952. doi: 10.1093/hmg/10.18.1945. [DOI] [PubMed] [Google Scholar]
  12. Chang W., Dynek J.N., Smith S. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Gene. Dev. 2003;17:1328–1333. doi: 10.1101/gad.1077103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chin L., Artandi S.E., Shen Q., Tam A., Lee S.L., Gottlieb G.J., Greider C.W., DePinho R.A. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527–538. doi: 10.1016/S0092-8674(00)80762-X. [DOI] [PubMed] [Google Scholar]
  14. Chong L., van Steensel B., Broccoli D., Erdjument-Bromage H., Hanish J., Tempst P., de Lange T. A human telomeric protein. Science. 1995;270:1663–1667. doi: 10.1126/science.270.5242.1663. [DOI] [PubMed] [Google Scholar]
  15. Colgin L.M., Baran K., Baumann P., Cech T.R., Reddel R.R. Human POT1 facilitates telomere elongation by telomerase. Curr. Biol. 2003;13:942–946. doi: 10.1016/S0960-9822(03)00339-7. [DOI] [PubMed] [Google Scholar]
  16. Colgin L.M., Wilkinson C., Englezou A., Kilian A., Robinson M.O., Reddel R.R. The hTERTalpha splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia. 2000;2:426–432. doi: 10.1038/sj.neo.7900112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cook B.D., Dynek J.N., Chang W., Shostak G., Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol. Cell Biol. 2002;22:332–342. doi: 10.1128/MCB.22.1.332-342.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Cooke H.J., Smith B.A. Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harbor Symp. Quant. Biol. 1986;51(Pt 1):213–219. doi: 10.1101/sqb.1986.051.01.026. [DOI] [PubMed] [Google Scholar]
  19. Counter C.M., Gupta J., Harley C.B., Leber B., Bacchetti S. Telomerase activity in normal leukocytes and in hematologic malignancies. Blood. 1995;85:2315–2320. [PubMed] [Google Scholar]
  20. d’Addadi Fagagna F., Reaper P.M., Clay-Farrace L., Fiegler H., Carr P., Von Zglinicki T., Saretzki G., Carter N.P., Jackson S.P. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–198. doi: 10.1038/nature02118. [DOI] [PubMed] [Google Scholar]
  21. Dynek J.N., Smith S. Resolution of sister telomere association is required for progression through mitosis. Science. 2004;304:97–100. doi: 10.1126/science.1094754. [DOI] [PubMed] [Google Scholar]
  22. Erdmann N., Liu Y., Harrington L. Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice. Proc. Natl. Acad. Sci. USA. 2004;101:6080–6085. doi: 10.1073/pnas.0401580101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Evans S.K., Lundblad V. Est1 and Cdc13 as comediators of telomerase access. Science. 1999;286:117–120. doi: 10.1126/science.286.5437.117. [DOI] [PubMed] [Google Scholar]
  24. Evans S.K., Lundblad V. The Est1 subunit of Saccharomyces cerevisiae telomerase makes multiple contributions to telomere length maintenance. Genetics. 2002;162:1101–1115. doi: 10.1093/genetics/162.3.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Forsythe H.L., Jarvis J.L., Turner J.W., Elmore L.W., Holt S.E. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J. Biol. Chem. 2001;276:15571–15574. doi: 10.1074/jbc.C100055200. [DOI] [PubMed] [Google Scholar]
  26. Garcia-Cao M., O’Sullivan R., Peters A.H., Jenuwein T., Blasco M.A. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat. Genet. 2004;36:94–99. doi: 10.1038/ng1278. [DOI] [PubMed] [Google Scholar]
  27. Griffith J., Bianchi A., de Lange T. TRF1 promotes parallel pairing of telomeric tracts in vitro. J. Mol. Biol. 1998;278:79–88. doi: 10.1006/jmbi.1998.1686. [DOI] [PubMed] [Google Scholar]
  28. Griffith J.D., Comeau L., Rosenfield S., Stansel R.M., Bianchi A., Moss H., de Lange T. Mammalian telomeres end in a large duplex loop. Cell. 1999;97:503–514. doi: 10.1016/S0092-8674(00)80760-6. [DOI] [PubMed] [Google Scholar]
  29. Hanaoka S., Nagadoi A., Yoshimura S., Aimoto S., Li B., de Lange T., Nishimura Y. NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains. J. Mol. Biol. 2001;312:167–175. doi: 10.1006/jmbi.2001.4924. [DOI] [PubMed] [Google Scholar]
  30. Harrington L. Those damaged telomeres! Curr. Opin. Genet. Dev. 2004;14:22–28. doi: 10.1016/j.gde.2003.12.007. [DOI] [PubMed] [Google Scholar]
  31. Hathcock K.S., Hemann M.T., Opperman K.K., Strong M.A., Greider C.W., Hodes R.J. Haploinsufficiency of mTR results in defects in telomere elongation. Proc. Natl. Acad. Sci. USA. 2002;99:3591–3596. doi: 10.1073/pnas.012549799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hemann M.T., Greider C.W. G-strand overhangs on telomeres in telomerase-deficient mouse cells. Nucleic Acids Res. 1999;27:3964–3969. doi: 10.1093/nar/27.20.3964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Hemann M.T., Strong M.A., Hao L.Y., Greider C.W. The shortest telomerenot average telomere lengthis critical for cell viability and chromosome stability. Cell. 2001;107:67–77. doi: 10.1016/S0092-8674(01)00504-9. [DOI] [PubMed] [Google Scholar]
  34. Holt S.E., Aisner D.L., Baur J., Tesmer V.M., Dy M., Ouellette M., Trager J.B., Morin G.B., Toft D.O., Shay J.W., Wright W.E., White M.A. Functional requirement of p23 and Hsp90 in telomerase complexes. Gene. Dev. 1999;13:817–826. doi: 10.1101/gad.13.7.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hsu H.L., Gilley D., Blackburn E.H., Chen D.J. Ku is associated with the telomere in mammals. Proc. Natl. Acad. Sci. USA. 1999;96:12454–12458. doi: 10.1073/pnas.96.22.12454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hsu H.L., Gilley D., Galande S.A., Hande M.P., Allen B., Kim S.H., Li G.C., Campisi J., Kohwi-Shigematsu T., Chen D.J. Ku acts in a unique way at the mammalian telomere to prevent end joining. Gene. Dev. 2000;14:2807–2812. doi: 10.1101/gad.844000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Iwano T., Tachibana M., Reth M., Shinkai Y. Importance of TRF1 for functional telomere structure. J. Biol. Chem. 2004;279:1442–1448. doi: 10.1074/jbc.M309138200. [DOI] [PubMed] [Google Scholar]
  38. Karlseder J., Broccoli D., Dai Y., Hardy S., de Lange T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science. 1999;283:1321–1325. doi: 10.1126/science.283.5406.1321. [DOI] [PubMed] [Google Scholar]
  39. Karlseder J., Kachatrian L., Takai H., Mercer K., Hingorani S., Jacks T., de Lange T. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol. Cell Biol. 2003;23:6533–6541. doi: 10.1128/MCB.23.18.6533-6541.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Karlseder J., Smogorzewska A., de Lange T. Senescence induced by altered telomere statenot telomere loss. Science. 2002;295:2446–2449. doi: 10.1126/science.1069523. [DOI] [PubMed] [Google Scholar]
  41. Kelleher C., Teixeira M.T., Forstemann K., Lingner J. Telomerase: biochemical considerations for enzyme and substrate. Trends Biochem. Sci. 2002;27:572–579. doi: 10.1016/S0968-0004(02)02206-5. [DOI] [PubMed] [Google Scholar]
  42. Kharbanda S., Kumar V., Dhar S., Pandey P., Chen C., Majumder P., Yuan Z.M., Whang Y., Strauss W., Pandita T.K., Weaver D., Kufe D. Regulation of the hTERT telomerase catalytic subunit by the c–Abl tyrosine kinase. Curr. Biol. 2000;10:568–575. doi: 10.1016/S0960-9822(00)00483-8. [DOI] [PubMed] [Google Scholar]
  43. Kim S.H., Han S., You Y.H., Chen D.J., Campisi J. The human telomere-associated protein TIN2 stimulates interactions between telomeric DNA tracts in vitro. EMBO Rep. 2003;4:685–691. doi: 10.1038/sj.embor.embor872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Kim S.H., Kaminker P., Campisi J. TIN2, a new regulator of telomere length in human cells. Nat. Genet. 1999;23:405–412. doi: 10.1038/70508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Kipling D., Cooke H.J. Hypervariable ultra-long telomeres in mice. Nature. 1990;347:400–402. doi: 10.1038/347400a0. [DOI] [PubMed] [Google Scholar]
  46. Li B., de Lange T. Rap1 affects the length and heterogeneity of human telomeres. Mol. Biol. Cell. 2003;14:5060–5068. doi: 10.1091/mbc.E03-06-0403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Li B., Oestreich S., de Lange T. Identification of human Rap1: implications for telomere evolution. Cell. 2000;101:471–483. doi: 10.1016/S0092-8674(00)80858-2. [DOI] [PubMed] [Google Scholar]
  48. Lindsey J., Mcgill N.I., Lindsey L.A., Green D.K., Cooke H.J. In vivo loss of telomeric repeats with age in humans. Mut. Res. 1991;256:45–48. doi: 10.1016/0921-8734(91)90032-7. [DOI] [PubMed] [Google Scholar]
  49. Liu K., Hodes R.J., Weng N. Cutting edge: telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation. J. Immunol. 2001;166:4826–4830. doi: 10.4049/jimmunol.166.8.4826. [DOI] [PubMed] [Google Scholar]
  50. Liu Y., Snow B.E., Hande M.P., Yeung D., Erdmann N.J., Wakeham A., Itie A., Siderovski D.P., Lansdorp P.M., Robinson M.O., Harrington L. The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo. Curr. Biol. 2000;10:1459–1462. doi: 10.1016/S0960-9822(00)00805-8. [DOI] [PubMed] [Google Scholar]
  51. Loayza D., De Lange T. POT1 as a terminal transducer of TRF1 telomere length control. Nature. 2003;424:1013–1018. doi: 10.1038/nature01688. [DOI] [PubMed] [Google Scholar]
  52. Makarov V.L., Hirose Y., Langmore J.P. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell. 1997;88:657–666. doi: 10.1016/S0092-8674(00)81908-X. [DOI] [PubMed] [Google Scholar]
  53. Masutomi K., Yu E.Y., Khurts S., Ben-Porath I., Currier J.L., Metz G.B., Brooks M.W., Kaneko S., Murakami S., DeCaprio J.A., Weinberg R.A., Stewart S.A., Hahn W.C. Telomerase maintains telomere structure in normal human cells. Cell. 2003;114:241–253. doi: 10.1016/S0092-8674(03)00550-6. [DOI] [PubMed] [Google Scholar]
  54. Matera A.G. Cajal bodies. Curr. Biol. 2003;13:R503. doi: 10.1016/S0960-9822(03)00438-X. [DOI] [PubMed] [Google Scholar]
  55. McClintock B. The stability of broken ends of chromosomes in zea mays. Genetics. 1941;26:234–282. doi: 10.1093/genetics/26.2.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. McElligott R., Wellinger R.J. The terminal structure of mammalian chromosomes. EMBO J. 1997;16:3705–3714. doi: 10.1093/emboj/16.12.3705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Meyerson M., Counter C.M., Eaton E.N., Ellisen L.W., Steiner P., Caddle S.D., Ziaugra L., Beijersbergen R.L., Davidoff M.J., Liu Q., Bacchetti S., Haber D.A., Weinberg R.A. hEST2, the putative human telomerase catalytic subunit geneis up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–795. doi: 10.1016/s0092-8674(00)80538-3. [DOI] [PubMed] [Google Scholar]
  58. Muller H.J. The remaking of chromosomes. Collecting Net. 1938;13:182–198. [Google Scholar]
  59. O’Connor M., Safari A., Liu D., Qin J., Songyang Z. The human Rap1 protein complex and modulation of telomere length. J. Biol. Chem. 2004;279:28585–28591. doi: 10.1074/jbc.M312913200. [DOI] [PubMed] [Google Scholar]
  60. Olovnikov A.M. A theory of marginotomy. J. Theor. Biol. 1973;41:181–190. doi: 10.1016/0022-5193(73)90198-7. [DOI] [PubMed] [Google Scholar]
  61. Oulton R., Harrington L. A human telomerase-associated nuclease. Mol. Biol. Cell. 2004;15:3244–3256. doi: 10.1091/mbc.E04-03-0178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Perrem K., Colgin L.M., Neumann A.A., Yeager T.R., Reddel R.R. Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 cells. Mol. Cell Biol. 2001;21:3862–3875. doi: 10.1128/MCB.21.12.3862-3875.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Reaper P.M., Di Fagagna F.D., Jackson S.P. Activation of the DNA Damage Response by Telomere Attrition: A Passage to Cellular Senescence. Cell Cycle. 2004;3:543–546. [PubMed] [Google Scholar]
  64. Reichenbach P., Hoss M., Azzalin C.M., Nabholz M., Bucher P., Lingner J. A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed. Curr. Biol. 2003;13:568–574. doi: 10.1016/S0960-9822(03)00173-8. [DOI] [PubMed] [Google Scholar]
  65. Sharma G.G., Hwang K.K., Pandita R.K., Gupta A., Dhar S., Parenteau J., Agarwal M., Worman H.J., Wellinger R.J., Pandita T.K. Human heterochromatin protein 1 isoforms HP1(Hsalpha) and HP1(Hsbeta) interfere with hTERT-telomere interactions and correlate with changes in cell growth and response to ionizing radiation. Mol. Cell Biol. 2003;23:8363–8376. doi: 10.1128/MCB.23.22.8363-8376.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Shay J.W., Bacchetti S. A survey of telomerase activity in human cancer. Eur. J. Cancer. 1997;33:787–791. doi: 10.1016/S0959-8049(97)00062-2. [DOI] [PubMed] [Google Scholar]
  67. Smith S., de Lange T. Tankyrase promotes telomere elongation in human cells. Curr. Biol. 2000;10:1299–1302. doi: 10.1016/S0960-9822(00)00752-1. [DOI] [PubMed] [Google Scholar]
  68. Smith S., Giriat I., Schmitt A., de Lange T. Tankyrasea poly(ADP-ribose) polymerase at human telomeres. Science. 1998;282:1484–1487. doi: 10.1126/science.282.5393.1484. [DOI] [PubMed] [Google Scholar]
  69. Smogorzewska A., Karlseder J., Holtgreve-Grez H., Jauch A., de Lange T. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr. Biol. 2002;12:1635–1644. doi: 10.1016/S0960-9822(02)01179-X. [DOI] [PubMed] [Google Scholar]
  70. Smogorzewska A., van Steensel B., Bianchi A., Oelmann S., Schaefer M.R., Schnapp G., Lange de T. Control of human telomere length by TRF1 and TRF2. Mol. Cell Biol. 2000;20:1659–1668. doi: 10.1128/MCB.20.5.1659-1668.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Snow B.E., Erdmann N., Cruickshank J., Goldman H., Gill R.M., Robinson M.O., Harrington L. Functional conservation of the telomerase protein Est1p in humans. Curr. Biol. 2003;13:698–704. doi: 10.1016/S0960-9822(03)00210-0. [DOI] [PubMed] [Google Scholar]
  72. Stansel R.M., de Lange T., Griffith J. T-loop assembly involves binding of TRF2 near the 3’telomeric overhang. EMBO J. 2001;20:5532–5540. doi: 10.1093/emboj/20.19.5532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Stewart S.A. Multiple levels of telomerase regulation. Mol. Interv. 2002;2:481–483. doi: 10.1124/mi.2.8.481. [DOI] [PubMed] [Google Scholar]
  74. Taggart A.K., Teng S.C., Zakian V.A. Est1p as a cell cycle-regulated activator of telomere-bound telomerase. Science. 2002;297:1023–1026. doi: 10.1126/science.1074968. [DOI] [PubMed] [Google Scholar]
  75. Takai H., Smogorzewska A., de Lange T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 2003;13:1549–1556. doi: 10.1016/S0960-9822(03)00542-6. [DOI] [PubMed] [Google Scholar]
  76. Teixeira M.T., Arneric M., Sperisen P., Lingner J. Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell. 2004;117:323–335. doi: 10.1016/s0092-8674(04)00334-4. [DOI] [PubMed] [Google Scholar]
  77. Tham W.H., Zakian V.A. Transcriptional silencing at Saccharomyces telomeres: implications for other organisms. Oncogene. 2002;21:512–521. doi: 10.1038/sj.onc.1205078. [DOI] [PubMed] [Google Scholar]
  78. Tommerup H., Dousmanis A., de Lange T. Unusual chromatin in human telomeres. Mol. Cell Biol. 1994;14:5777–5785. doi: 10.1128/mcb.14.9.5777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. van Steensel B., de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature. 1997;385:740–743. doi: 10.1038/385740a0. [DOI] [PubMed] [Google Scholar]
  80. van Steensel B., Smogorzewska A., de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998;92:401–413. doi: 10.1016/S0092-8674(00)80932-0. [DOI] [PubMed] [Google Scholar]
  81. Vega L.R., Mateyak M.K., Zakian V.A. Getting to the end: telomerase access in yeast and humans. Nat. Rev. Mol. Cell Biol. 2003;4:948–959. doi: 10.1038/nrm1256. [DOI] [PubMed] [Google Scholar]
  82. Wong J.M., Kusdra L., Collins K. Subnuclear shuttling of human telomerase induced by transformation and DNA damage. Nat. Cell Biol. 2002;4:731–736. doi: 10.1038/ncb846. [DOI] [PubMed] [Google Scholar]
  83. Wright W.E., Tesmer V.M., Huffman K.E., Levene S.D., Shay J.W. Normal human chromosomes have long G-rich telomeric overhangs at one end. Gene. Dev. 1997;11:2801–2809. doi: 10.1101/gad.11.21.2801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Ye J.Z., De Lange T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat. Genet. 2004;36:618–623. doi: 10.1038/ng1360. [DOI] [PubMed] [Google Scholar]
  85. Yi X., White D.M., Aisner D.L., Baur J.A., Wright W.E., Shay J.W. An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity. Neoplasia. 2000;2:433–440. doi: 10.1038/sj.neo.7900113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Zhou X.Z., Lu K.P. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell. 2001;107:347–359. doi: 10.1016/S0092-8674(01)00538-4. [DOI] [PubMed] [Google Scholar]
  87. Zhu L., Hathcock K.S., Hande P., Lansdorp P.M., Seldin M.F., Hodes R.J. Telomere length regulation in mice is linked to a novel chromosome locus. Proc. Natl. Acad. Sci. USA. 1998;95:8648–8653. doi: 10.1073/pnas.95.15.8648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Zhu X.D., Kuster B., Mann M., Petrini J.H., de Lange T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat. Genet. 2000;25:347–352. doi: 10.1038/77139. [DOI] [PubMed] [Google Scholar]
  89. Zhu X.D., Niedernhofer L., Kuster B., Mann M., Hoeijmakers J.H., de Lange T. ERCC1/XPF removes the 3’overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol. Cell. 2003;12:1489–1498. doi: 10.1016/S1097-2765(03)00478-7. [DOI] [PubMed] [Google Scholar]
  90. Zhu Y., Tomlinson R.L., Lukowiak A.A., Terns R.M., Terns M.P. Telomerase RNA accumulates in Cajal bodies in human cancer cells. Mol. Biol. Cell. 2004;15:81–90. doi: 10.1091/mbc.E03-07-0525. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cytotechnology are provided here courtesy of Springer Science+Business Media B.V.

RESOURCES