, Volume 114, Issue 3, pp 135–145 | Cite as

The mechanism of telomere protection: a comparison between Drosophila and humans

  • Giovanni Cenci
  • Laura Ciapponi
  • Maurizio Gatti


Drosophila telomeres are maintained by transposition of specialized retrotransposons rather than by telomerase activity, and their stability is independent of the sequence of DNA termini. Recent studies have identified several proteins that protect Drosophila telomeres from fusion events. These proteins include the telomere capping factors HP1/ORC-associated protein (HOAP) and heterochromatin protein 1 (HP1), the Rad50 and Mre11 DNA repair proteins that are required for HOAP and HP1 localization at telomeres, and the ATM kinase. Another telomere-protecting factor identified in Drosophila is UbcD1, a polypeptide highly homologous to class I ubiquitin-conjugating E2 enzymes. In addition, it has been shown that HP1 and both components of the Drosophila Ku70/80 heterodimer act as negative regulators of telomere length. Except for HOAP, all these proteins are conserved in humans and are associated with human telomeres. Collectively, these results indicate that Drosophila is an excellent model system for the analysis of the mechanisms of telomere maintenance. In past and current studies, 15 Drosophila genes have been identified that prevent telomeric fusion, and it has been estimated that the Drosophila genome contains at least 40 genes required for telomere protection. We believe that the molecular characterization of these genes will lead to identification of many novel human genes with roles in telomere maintenance.


Telomere Length Polytene Chromosome Mitotic Chromosome Telomere Maintenance Telomere Elongation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are grateful to Harald Biessmann for communicating results prior to publication. L.C. was supported by the “Rientro Cervelli” program by MIUR. This work was supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to M.G.


  1. Abad JP, De Pablos B, Osoegawa k, De Jong PJ, Martin-Gallardo A, Villasante A (2004) TAHRE, a novel telomeric retrotransposon from Drosophila melanogaster, reveals the origin of Drosophila telomeres. Mol Biol Evol 21:1620–1624CrossRefPubMedGoogle Scholar
  2. Aguilar RC, Wendland B (2003) Ubiquitin: not just for proteasomes anymore. Curr Opin Cell Biol 15:184–190CrossRefPubMedGoogle Scholar
  3. Badugu R, Shareef MM, Kellum R (2003) Novel Drosophila heterochromatin protein 1 (HP1)/origin recognition complex-associated protein (HOAP) repeat motif in HP1/HOAP interactions and chromocenter associations. J Biol Chem 278:34491–34498CrossRefPubMedGoogle Scholar
  4. Bai Y, Murnane JP (2003) Telomere instability in a human tumor cell line expressing NBS1 with mutations at sites phosphorylated by ATM. Mol Cancer Res 1:1058–1069PubMedGoogle Scholar
  5. Bi X, Wei SD, Rong YS (2004) Telomere protection without a telomerase: the role of ATM and Mre11 in Drosophila telomere maintenance. Curr Biol 14:1348–1353CrossRefPubMedGoogle Scholar
  6. Biessmann H, Mason JM (1988) Progressive loss of DNA sequences from terminal chromosome deficiencies in Drosophila melanogaster. EMBO J 7:1081–1086PubMedGoogle Scholar
  7. Biessmann H, Mason JM (2003) Telomerase-independent mechanisms of telomere elongation. Cell Mol Life Sci 60:2325–2333CrossRefPubMedGoogle Scholar
  8. Biessmann H, Carter SB, Mason JM (1990) Chromosome ends in Drosophila without telomeric DNA sequences. Proc Natl Acad Sci U S A 87:1758–1761PubMedCrossRefGoogle Scholar
  9. Biessmann H, Champion LE, O'Hair M, Ikenaga K, Kasravi B, Mason JM (1992) Frequent transpositions of Drosophila melanogaster HeT-A transposable elements to receding chromosome ends. EMBO J 11:4459–4469PubMedGoogle Scholar
  10. Biessmann H, Prasad S, F. WM, Mason JM (2005) Euchromatic and Heterochromatic domains at Drosophila telomeres. Biochem Cell Biol, in pressGoogle Scholar
  11. Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR (1995) Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14:4240–4248PubMedGoogle Scholar
  12. Cenci G, Rawson RB, Belloni G, Castrillon DH, Tudor M, Petrucci R, Goldberg ML, Wasserman SA, Gatti M (1997) UbcD1, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior. Genes Dev 11:863–875PubMedCrossRefGoogle Scholar
  13. Cenci G, Siriaco G, Gatti M (2003a) The role of HeT-A and TART retrotransposons in Drosophila telomere capping. Genetica 117:311–318CrossRefPubMedGoogle Scholar
  14. Cenci G, Siriaco G, Raffa GD, Kellum R, Gatti M (2003b) The Drosophila HOAP protein is required for telomere capping. Nat Cell Biol 5:82–84CrossRefPubMedGoogle Scholar
  15. Ciapponi L, Cenci G, Ducau J, Flores C, Johnson-Schlitz D, Gorsky MM, Engels WR, Gatti M (2004) The Drosophila Mre11/Rad50 Complex is required to prevent both telomeric fusion and chromosome breakage. Curr Biol 14:1360–1366CrossRefPubMedGoogle Scholar
  16. d'Adda di Fagagna F, Teo SH, Jackson SP (2004) Functional links between telomeres and proteins of the DNA-damage response. Genes Dev 18:1781–1799CrossRefPubMedGoogle Scholar
  17. D'Amours D, Jackson SP (2002) The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3:317–327CrossRefPubMedGoogle Scholar
  18. de Jager M, van Noort J, van Gent DC, Dekker C, Kanaar R, Wyman C (2001) Human Rad50/Mre11 is a flexible complex that can tether DNA ends. Mol Cell 8:1129–1135CrossRefPubMedGoogle Scholar
  19. de Lange T (1995) Telomere dinamics and genome instability in human cancer. In: Blackburn EH, Greider W (eds) Telomeres. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 265–293Google Scholar
  20. de Lange T (2002) Protection of mammalian telomeres. Oncogene 21:532–540CrossRefPubMedGoogle Scholar
  21. de Lange T (2004) Opinion: t-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5:323–329CrossRefPubMedGoogle Scholar
  22. Downs JA, Jackson SP (2004) A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol 5:367–378CrossRefPubMedGoogle Scholar
  23. Dunham MA, Neumann AA, Fasching CL, Reddel RR (2000) Telomere maintenance by recombination in human cells. Nat Genet 26:447–450CrossRefPubMedGoogle Scholar
  24. Eissenberg JC, Elgin SC (2000) The HP1 protein family: getting a grip on chromatin. Curr Opin Genet Dev 10:204–210CrossRefPubMedGoogle Scholar
  25. Fanti L, Giovinazzo G, Berloco M, Pimpinelli S (1998) The heterochromatin protein 1 prevents telomere fusions in Drosophila. Mol Cell 2:527–538CrossRefPubMedGoogle Scholar
  26. Fanti L, Berloco M, Piacentini L, Pimpinelli S (2003) Chromosomal distribution of heterochromatin protein 1 (HP1) in Drosophila: a cytological map of euchromatic HP1 binding sites. Genetica 117:135–147CrossRefPubMedGoogle Scholar
  27. 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 36:94–99CrossRefPubMedGoogle Scholar
  28. Gatti M, Baker BS (1989) Genes controlling essential cell-cycle functions in Drosophila melanogaster. Genes Dev 3:438–453PubMedCrossRefGoogle Scholar
  29. Gobulovsky MD, Konev AY, Walter MF, Biessman H, Mason JM (2001) Terminal retrotransposons activate a subtelomeric white transgene at the 2L telomere in Drosophila. Genetics 158:1111–1123PubMedGoogle Scholar
  30. 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 97:503–514CrossRefPubMedGoogle Scholar
  31. 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 14:1621–1631CrossRefPubMedGoogle Scholar
  32. Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, Li GC, Campisi J, Kohwi-Shigematsu T, Chen DJ (2000) Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev 14:2807–2812CrossRefPubMedGoogle Scholar
  33. Jaco I, Munoz P, Blasco MA (2004) Role of human Ku86 in telomere length maintenance and telomere capping. Cancer Res 64:7271–7278CrossRefPubMedGoogle Scholar
  34. James TC, Eissenberg JC, Craig C, Dietrich V, Hobson A, Elgin SC (1989) Distribution patterns of HP1, a heterochromatin-associated nonhistone chromosomal protein of Drosophila. Eur J Cell Biol 50:170–180PubMedGoogle Scholar
  35. Kahn T, Savitsky M, Georgiev P (2000) Attachment of HeT-A sequences to chromosomal termini in Drosophila melanogaster may occur by different mechanisms. Mol Cell Biol 20:7634–7642CrossRefPubMedGoogle Scholar
  36. Karlseder J, Hoke K, Mirzoeva OK, Bakkenist C, Kastan MB, Petrini JH, de Lange T (2004) The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol 2:E240CrossRefPubMedGoogle Scholar
  37. Kasravi A, Walter MF, Brand S, Mason JM, Biessmann H (1999) Molecular cloning and tissue-specific expression of the mutator2 gene (mu2) in Drosophila melanogaster. Genetics 152:1025–1035PubMedGoogle Scholar
  38. Kim SH, Kaminker P, Campisi J (1999) TIN2, a new regulator of telomere length in human cells. Nat Genet 23:405–412CrossRefPubMedGoogle Scholar
  39. Kim SH, Kaminker P, Campisi J (2002) Telomeres, aging and cancer: in search of a happy ending. Oncogene 21:503–511CrossRefPubMedGoogle Scholar
  40. Kim SH, Beausejour C, Davalos AR, Kaminker P, Heo SJ, Campisi J (2004) TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem 279:43799–43804CrossRefPubMedGoogle Scholar
  41. Levis RW (1989) Viable deletions of a telomere from a Drosophila chromosome. Cell 58:791–801CrossRefPubMedGoogle Scholar
  42. Liu D, O'Connor MS, Qin J, Songyang Z (2004a) Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 279:51338–51342CrossRefPubMedGoogle Scholar
  43. 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 6:673–680CrossRefPubMedGoogle Scholar
  44. Loayza D, de Lange T (2003) POT1 as a terminal transducer of TRF1 telomere length control. Nature 423:1013–1018CrossRefPubMedGoogle Scholar
  45. Maser RS, DePinho RA (2002) Connecting chromosomes, crisis, and cancer. Science 297:565–569CrossRefPubMedGoogle Scholar
  46. Mason JM, Biessmann H (1995) The unusual telomeres of Drosophila. Trends Genet 11:58–62CrossRefPubMedGoogle Scholar
  47. Mason JM, Strobel E, Green MM (1984) mu-2: mutator gene in Drosophila that potentiates the induction of terminal deficiencies. Proc Natl Acad Sci U S A 81:6090–6094PubMedCrossRefGoogle Scholar
  48. Mason JM, Champion LE, Hook G (1997) Germ-line effects of a mutator, mu2, in Drosophila melanogaster. Genetics 146:1381–1397PubMedGoogle Scholar
  49. Melnikova L, Georgiev P (2002) Enhancer of terminal gene conversion, a new mutation in Drosophila melanogaster that induces telomere elongation by gene conversion. Genetics 162:1301–1312PubMedGoogle Scholar
  50. Melnikova L, Biessmann H, Georgiev P (2005) The Ku protein complex is involved in length regulation of Drosophila telomeres. Genetics, in pressGoogle Scholar
  51. Mikhailovsky S, Belenkaya T, Georgiev P (1999) Broken chromosomal ends can be elongated by conversion in Drosophila melanogaster. Chromosoma 108:114–120CrossRefPubMedGoogle Scholar
  52. Muller HJ (1938) The remaking of chromosomes. Collecting Net 13:181–195Google Scholar
  53. Myung K, Ghosh G, Fattah FJ, Li G, Kim H, Dutia A, Pak E, Smith S, Hendrickson EA (2004) Regulation of telomere length and suppression of genomic instability in human somatic cells by Ku86. Mol Cell Biol 24:5050–5059CrossRefPubMedGoogle Scholar
  54. Nugent CI, Lundblad V (1998) The telomerase reverse transcriptase: components and regulation. Genes Dev 12:1073–1085PubMedGoogle Scholar
  55. Oikemus SR, McGinnis N, Queiroz-Machado J, Tukachinsky H, Takada S, Sunkel CE, Brodsky MH (2004) Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect. Genes Dev 18:1850–1861CrossRefPubMedGoogle Scholar
  56. Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA (2002) Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J Biol Chem 277:41110–41119CrossRefPubMedGoogle Scholar
  57. Opresko PL, Otterlei M, Graakjaer J, Bruheim P, Dawut L, Kolvraa S, May A, Seidman MM, Bohr VA (2004) The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol Cell 14:763–774CrossRefPubMedGoogle Scholar
  58. Pak DT, Pflumm M, Chesnokov I, Huang DW, Kellum R, Marr J, Romanowski P, Botchan MR (1997) Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes. Cell 91:311–323CrossRefPubMedGoogle Scholar
  59. Pandita TK (2002) ATM function and telomere stability. Oncogene 21:611–618CrossRefPubMedGoogle Scholar
  60. Pardue M-L (1995) Drosophila telomeres: another way to end it all. In: Blackburn EH, Greider CW (eds) Telomeres. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY pp 339–370Google Scholar
  61. Pardue ML, DeBaryshe PG (2003) Retrotransposons provide an evolutionarily robust non-telomerase mechanism to maintain telomeres. Annu Rev Genet 37:485–511CrossRefPubMedGoogle Scholar
  62. Perrini B, Piacentini L, Fanti L, Altieri F, Chichiarelli S, Berloco M, Turano C, Ferraro A, Pimpinelli S (2004) HP1 controls telomere capping, telomere elongation, and telomere silencing by two different mechanisms in Drosophila. Mol Cell 15:467–476CrossRefPubMedGoogle Scholar
  63. Queiroz-Machado J, Perdigao J, Simoes-Carvalho P, Herrmann S, Sunkel CE (2001) tef: a mutation that causes telomere fusion and severe genome rearrangements in Drosophila melanogaster. Chromosoma 110:10–23PubMedCrossRefGoogle Scholar
  64. Rashkova S, Karam SE, Kellum R, Pardue ML (2002) Gag proteins of the two Drosophila telomeric retrotransposons are targeted to chromosome ends. J Cell Biol 159:397–402CrossRefPubMedGoogle Scholar
  65. Savitsky M, Kravchuk O, Melnikova L, Georgiev P (2002) Heterochromatin protein 1 is involved in control of telomere elongation in Drosophila melanogaster. Mol Cell Biol 22:3204–3218CrossRefPubMedGoogle Scholar
  66. Shareef MM, King C, Damaj M, Badagu R, Huang DW, Kellum R (2001) Drosophila heterochromatin protein 1 (HP1)/origin recognition complex (ORC) protein is associated with HP1 and ORC and functions in heterochromatin-induced silencing. Mol Biol Cell 12:1671–1685PubMedGoogle Scholar
  67. Sharma GG, Hwang KK, Pandita RK, Gupta A, Dhar S, Parenteau J, Agarwal M, Worman HJ, Wellinger RJ, Pandita TK (2003) 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 23:8363–8376CrossRefPubMedGoogle Scholar
  68. Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3:155–168CrossRefPubMedGoogle Scholar
  69. Silva E, Tiong S, Pedersen M, Homola EM, Royou A, Fasulo B, Siriaco G, Campbell SD (2004) ATM is required for telomere maintenance and chromosome stability during Drosophila development. Curr Biol 14:1341–1347CrossRefPubMedGoogle Scholar
  70. Siriaco GM, Cenci G, Haoudi A, Champion LE, Zhou C, Gatti M, Mason JM (2002) Telomere elongation (Tel), a new mutation in Drosophila melanogaster that produces long telomeres. Genetics 160:235–245PubMedGoogle Scholar
  71. Smogorzewska A, de Lange T (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem 73:177–208CrossRefPubMedGoogle Scholar
  72. Smogorzewska A, Karlseder J, Holtgreve-Grez H, Jauch A, de Lange T (2002) DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr Biol 12:1635–1644CrossRefPubMedGoogle Scholar
  73. Smothers JF, Henikoff S (2001) The hinge and chromo shadow domain impart distinct targeting of HP1-like proteins. Mol Cell Biol 21:2555–2569CrossRefPubMedGoogle Scholar
  74. Song K, Jung D, Jung Y, Lee SG, Lee I (2000) Interaction of human Ku70 with TRF2. FEBS Lett 481:81–85CrossRefPubMedGoogle Scholar
  75. Song YH, Mirey G, Betson M, Haber DA, Settleman J (2004) The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development. Curr Biol 14:1354–1359CrossRefPubMedGoogle Scholar
  76. Tarsounas M, Munoz P, Claas A, Smiraldo PG, Pittman DL, Blasco MA, West SC (2004) Telomere Maintenance Requires the RAD51D recombination/repair protein. Cell 117:337–347CrossRefPubMedGoogle Scholar
  77. van Steensel B, de Lange T (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385:740–743CrossRefPubMedGoogle Scholar
  78. van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92:401–413CrossRefPubMedGoogle Scholar
  79. Veldman T, Etheridge KT, Counter CM (2004) Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Curr Biol 14:2264–2270CrossRefPubMedGoogle Scholar
  80. Wu G, Lee WH, Chen PL (2000) NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres. J Biol Chem 275:30618–30622CrossRefPubMedGoogle Scholar
  81. Yang Q, Zheng YL, Harris CC (2005) POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 25:1070–1080CrossRefPubMedGoogle Scholar
  82. Ye JZ, de Lange T (2004) TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 36:618–623CrossRefPubMedGoogle Scholar
  83. 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 279:47264–47271CrossRefPubMedGoogle Scholar
  84. 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 18:1649–1654CrossRefPubMedGoogle Scholar
  85. Zhou XZ, Lu KP (2001) The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 107:347–359CrossRefPubMedGoogle Scholar
  86. 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 25:347–352CrossRefPubMedGoogle Scholar
  87. Zhu XD, Niedernhofer L, Kuster B, Mann M, Hoeijmakers JH, de Lange T (2003) ERCC1/XPF removes the 3′ overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol Cell 12:1489–1498CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Giovanni Cenci
    • 1
    • 2
  • Laura Ciapponi
    • 1
  • Maurizio Gatti
    • 1
    • 3
  1. 1.Dipartimento di Genetica e Biologia MolecolareUniversità di Roma La SapienzaRomeItaly
  2. 2.Dipartimento di Scienze e Tecnologie Biologiche ed AmbientaliUniversità di LecceLecceItaly
  3. 3.Istituto di Biologia e Patologia Molecolare del CNRRomeItaly

Personalised recommendations