Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Chromosoma Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  • 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 21:1620–1624

    Article  PubMed  CAS  Google Scholar 

  • Aguilar RC, Wendland B (2003) Ubiquitin: not just for proteasomes anymore. Curr Opin Cell Biol 15:184–190

    Article  PubMed  CAS  Google Scholar 

  • 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 278:34491–34498

    Article  PubMed  CAS  Google Scholar 

  • 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 1:1058–1069

    PubMed  CAS  Google Scholar 

  • Bi X, Wei SD, Rong YS (2004) Telomere protection without a telomerase: the role of ATM and Mre11 in Drosophila telomere maintenance. Curr Biol 14:1348–1353

    Article  PubMed  CAS  Google Scholar 

  • Biessmann H, Mason JM (1988) Progressive loss of DNA sequences from terminal chromosome deficiencies in Drosophila melanogaster. EMBO J 7:1081–1086

    PubMed  CAS  Google Scholar 

  • Biessmann H, Mason JM (2003) Telomerase-independent mechanisms of telomere elongation. Cell Mol Life Sci 60:2325–2333

    Article  PubMed  CAS  Google Scholar 

  • Biessmann H, Carter SB, Mason JM (1990) Chromosome ends in Drosophila without telomeric DNA sequences. Proc Natl Acad Sci U S A 87:1758–1761

    Article  PubMed  CAS  Google Scholar 

  • 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 11:4459–4469

    PubMed  CAS  Google Scholar 

  • Biessmann H, Prasad S, F. WM, Mason JM (2005) Euchromatic and Heterochromatic domains at Drosophila telomeres. Biochem Cell Biol, in press

  • Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR (1995) Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14:4240–4248

    PubMed  CAS  Google Scholar 

  • 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 11:863–875

    Article  PubMed  CAS  Google Scholar 

  • Cenci G, Siriaco G, Gatti M (2003a) The role of HeT-A and TART retrotransposons in Drosophila telomere capping. Genetica 117:311–318

    Article  PubMed  CAS  Google Scholar 

  • Cenci G, Siriaco G, Raffa GD, Kellum R, Gatti M (2003b) The Drosophila HOAP protein is required for telomere capping. Nat Cell Biol 5:82–84

    Article  PubMed  CAS  Google Scholar 

  • 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 14:1360–1366

    Article  PubMed  CAS  Google Scholar 

  • d'Adda di Fagagna F, Teo SH, Jackson SP (2004) Functional links between telomeres and proteins of the DNA-damage response. Genes Dev 18:1781–1799

    Article  PubMed  Google Scholar 

  • D'Amours D, Jackson SP (2002) The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3:317–327

    Article  PubMed  CAS  Google Scholar 

  • 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 8:1129–1135

    Article  PubMed  Google Scholar 

  • 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 265–293

    Google Scholar 

  • de Lange T (2002) Protection of mammalian telomeres. Oncogene 21:532–540

    Article  PubMed  Google Scholar 

  • de Lange T (2004) Opinion: t-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5:323–329

    Article  PubMed  CAS  Google Scholar 

  • Downs JA, Jackson SP (2004) A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol 5:367–378

    Article  PubMed  CAS  Google Scholar 

  • Dunham MA, Neumann AA, Fasching CL, Reddel RR (2000) Telomere maintenance by recombination in human cells. Nat Genet 26:447–450

    Article  PubMed  CAS  Google Scholar 

  • Eissenberg JC, Elgin SC (2000) The HP1 protein family: getting a grip on chromatin. Curr Opin Genet Dev 10:204–210

    Article  PubMed  CAS  Google Scholar 

  • Fanti L, Giovinazzo G, Berloco M, Pimpinelli S (1998) The heterochromatin protein 1 prevents telomere fusions in Drosophila. Mol Cell 2:527–538

    Article  PubMed  CAS  Google Scholar 

  • 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 117:135–147

    Article  PubMed  CAS  Google Scholar 

  • 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 36:94–99

    Article  PubMed  CAS  Google Scholar 

  • Gatti M, Baker BS (1989) Genes controlling essential cell-cycle functions in Drosophila melanogaster. Genes Dev 3:438–453

    Article  PubMed  CAS  Google Scholar 

  • 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 158:1111–1123

    PubMed  Google Scholar 

  • 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 97:503–514

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 14:2807–2812

    Article  PubMed  CAS  Google Scholar 

  • Jaco I, Munoz P, Blasco MA (2004) Role of human Ku86 in telomere length maintenance and telomere capping. Cancer Res 64:7271–7278

    Article  PubMed  CAS  Google Scholar 

  • 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 50:170–180

    PubMed  CAS  Google Scholar 

  • 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 20:7634–7642

    Article  PubMed  CAS  Google Scholar 

  • 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:E240

    Article  PubMed  CAS  Google Scholar 

  • 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 152:1025–1035

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kim SH, Kaminker P, Campisi J (2002) Telomeres, aging and cancer: in search of a happy ending. Oncogene 21:503–511

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Levis RW (1989) Viable deletions of a telomere from a Drosophila chromosome. Cell 58:791–801

    Article  PubMed  CAS  Google Scholar 

  • Liu D, O'Connor MS, Qin J, Songyang Z (2004a) Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 279:51338–51342

    Article  PubMed  CAS  Google Scholar 

  • 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 6:673–680

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Maser RS, DePinho RA (2002) Connecting chromosomes, crisis, and cancer. Science 297:565–569

    Article  PubMed  CAS  Google Scholar 

  • Mason JM, Biessmann H (1995) The unusual telomeres of Drosophila. Trends Genet 11:58–62

    Article  PubMed  CAS  Google Scholar 

  • 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 81:6090–6094

    Article  PubMed  CAS  Google Scholar 

  • Mason JM, Champion LE, Hook G (1997) Germ-line effects of a mutator, mu2, in Drosophila melanogaster. Genetics 146:1381–1397

    PubMed  CAS  Google Scholar 

  • Melnikova L, Georgiev P (2002) Enhancer of terminal gene conversion, a new mutation in Drosophila melanogaster that induces telomere elongation by gene conversion. Genetics 162:1301–1312

    PubMed  CAS  Google Scholar 

  • Melnikova L, Biessmann H, Georgiev P (2005) The Ku protein complex is involved in length regulation of Drosophila telomeres. Genetics, in press

  • Mikhailovsky S, Belenkaya T, Georgiev P (1999) Broken chromosomal ends can be elongated by conversion in Drosophila melanogaster. Chromosoma 108:114–120

    Article  PubMed  CAS  Google Scholar 

  • Muller HJ (1938) The remaking of chromosomes. Collecting Net 13:181–195

    Google Scholar 

  • 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 24:5050–5059

    Article  PubMed  Google Scholar 

  • Nugent CI, Lundblad V (1998) The telomerase reverse transcriptase: components and regulation. Genes Dev 12:1073–1085

    PubMed  CAS  Google Scholar 

  • 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 18:1850–1861

    Article  PubMed  CAS  Google Scholar 

  • 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 277:41110–41119

    Article  PubMed  CAS  Google Scholar 

  • 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 14:763–774

    Article  PubMed  CAS  Google Scholar 

  • 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 91:311–323

    Article  PubMed  CAS  Google Scholar 

  • Pandita TK (2002) ATM function and telomere stability. Oncogene 21:611–618

    Article  PubMed  CAS  Google Scholar 

  • 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 339–370

    Google Scholar 

  • Pardue ML, DeBaryshe PG (2003) Retrotransposons provide an evolutionarily robust non-telomerase mechanism to maintain telomeres. Annu Rev Genet 37:485–511

    Article  PubMed  CAS  Google Scholar 

  • 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 15:467–476

    Article  PubMed  CAS  Google Scholar 

  • 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 110:10–23

    Article  PubMed  CAS  Google Scholar 

  • 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 159:397–402

    Article  PubMed  CAS  Google Scholar 

  • 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 22:3204–3218

    Article  PubMed  CAS  Google Scholar 

  • 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 12:1671–1685

    PubMed  CAS  Google Scholar 

  • 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 23:8363–8376

    Article  PubMed  CAS  Google Scholar 

  • Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3:155–168

    Article  PubMed  CAS  Google Scholar 

  • 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 14:1341–1347

    Article  PubMed  CAS  Google Scholar 

  • 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 160:235–245

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 12:1635–1644

    Article  PubMed  CAS  Google Scholar 

  • Smothers JF, Henikoff S (2001) The hinge and chromo shadow domain impart distinct targeting of HP1-like proteins. Mol Cell Biol 21:2555–2569

    Article  PubMed  CAS  Google Scholar 

  • Song K, Jung D, Jung Y, Lee SG, Lee I (2000) Interaction of human Ku70 with TRF2. FEBS Lett 481:81–85

    Article  PubMed  CAS  Google Scholar 

  • 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 14:1354–1359

    Article  PubMed  CAS  Google Scholar 

  • Tarsounas M, Munoz P, Claas A, Smiraldo PG, Pittman DL, Blasco MA, West SC (2004) Telomere Maintenance Requires the RAD51D recombination/repair protein. Cell 117:337–347

    Article  PubMed  CAS  Google Scholar 

  • van Steensel B, de Lange T (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385:740–743

    Article  PubMed  Google Scholar 

  • van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92:401–413

    Article  PubMed  Google Scholar 

  • Veldman T, Etheridge KT, Counter CM (2004) Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Curr Biol 14:2264–2270

    Article  PubMed  CAS  Google Scholar 

  • 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 275:30618–30622

    Article  PubMed  CAS  Google Scholar 

  • Yang Q, Zheng YL, Harris CC (2005) POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 25:1070–1080

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 279:47264–47271

    Article  PubMed  CAS  Google Scholar 

  • 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 18:1649–1654

    Article  PubMed  CAS  Google Scholar 

  • Zhou XZ, Lu KP (2001) The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 107:347–359

    Article  PubMed  CAS  Google Scholar 

  • 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 25:347–352

    Article  PubMed  CAS  Google Scholar 

  • 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 12:1489–1498

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Dipartimento di Genetica e Biologia Molecolare, Università di Roma La Sapienza, Piazzale A. Moro, 5, 00185, Rome, Italy

    Giovanni Cenci, Laura Ciapponi & Maurizio Gatti

  2. Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università di Lecce, Lecce, Italy

    Giovanni Cenci

  3. Istituto di Biologia e Patologia Molecolare del CNR, Rome, Italy

    Maurizio Gatti

Authors
  1. Giovanni Cenci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Ciapponi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maurizio Gatti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maurizio Gatti.

Additional information

Communicated by E. Nigg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cenci, G., Ciapponi, L. & Gatti, M. The mechanism of telomere protection: a comparison between Drosophila and humans. Chromosoma 114, 135–145 (2005). https://doi.org/10.1007/s00412-005-0005-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00412-005-0005-9

Keywords

Search

Navigation