In most organisms, telomeres consist of repetitive G-rich sequences that are elongated by a specific reverse transcriptase, telomerase. A large number of proteins are recruited by these terminal repeats, forming specialized structures that regulate telomerase activity and protect telomeres from degradation and recombination. Drosophila lacks telomerase and telomere length is maintained by transposition of three specialized retrotransposons. In addition, unlike yeast and mammals, Drosophila telomeres are epigenetically determined, sequence-independent structures. However, several proteins required for Drosophila telomere behavior are evolutionarily conserved. These include the Mre11-Rad50-Nbs (MRN) complex and the Ataxia Telangiectasia Mutated (ATM) kinase, which are required to prevent telomeric fusions. In addition, recent studies have provided evidence that Drosophila uncapped telomeres elicit a DNA damage response (DDR) just as dysfunctional yeast and human telomeres. Uncapped Drosophila telomeres also activate the spindle assembly checkpoint (SAC) by recruiting the SAC kinase BubR1. Telomere-induced DDR and SAC both require the wild type function of the MRN complex. In addition, while DDR is mediated by ATR kinase, SAC activation requires both the ATM and ATR activities. These results indicate that the DNA repair systems play multiple roles at Drosophila telomeres, highlighting the importance of this model organism for investigations on the relationships between DNA repair and telomere maintenance.

1.
Aagaard L, Schmid M, Warburton P, Jenuwein T: Mitotic phosphorylation of SUV39H1, a novel component of active centromeres, coincides with transient accumulation at mammalian centromeres. J Cell Sci 113:817–829 (2000).
2.
Ahmad K, Golic KG: Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics 151:1041–1051 (1999).
3.
Badugu R, Shareef MM, Kellum R: 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 (2003).
4.
Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, et al: Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86:159–171 (1996).
5.
Bender CF, Sikes ML, Sullivan R, Huye LE, Le Beau MM, et al: Cancer predisposition and hematopoietic failure in Rad50(S/S) mice. Genes Dev 16:2237–2251 (2002).
6.
Bi X, Wei SD, Rong YS: Telomere protection without a telomerase: the role of ATM and Mre11 in Drosophila telomere maintenance. Curr Biol 14:1348–1353 (2004).
7.
Bi X, Gong M, Srikanta D, Rong YS: Drosophila ATM and Mre11 are essential for the G2/M checkpoint induced by low-dose irradiation. Genetics 171:845–847 (2005a).
8.
Bi X, Srikanta D, Fanti L, Pimpinelli S, Badugu R, et al: Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance. Proc Natl Acad Sci USA 102:15167–15172 (2005b).
9.
Brodsky MH, Nordstrom W, Tsang G, Kwan E, Rubin GM, Abrams JM: Drosophila p53 binds a damage response element at the reaper locus. Cell 101:103–113 (2000a).
10.
Brodsky MH, Sekelsky JJ, Tsang G, Hawley RS, Rubin GM: mus304 encodes a novel DNA damage checkpoint protein required during Drosophila development. Genes Dev 14:666–678 (2000b).
11.
Celli GB, de Lange T: DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat Cell Biol 7:712–718 (2005).
12.
Cenci G, Rawson RB, Belloni G, Castrillon DH, Tudor M, et al: UbcD1, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior. Genes Dev 11:863–875 (1997).
13.
Cenci G, Siriaco G, Gatti M: The role of HeT-A and TART retrotransposons in Drosophila telomere capping. Genetica 117:311–318 (2003a).
14.
Cenci G, Siriaco G, Raffa GD, Kellum R, Gatti M: The Drosophila HOAP protein is required for telomere capping. Nat Cell Biol 5:82–84 (2003b).
15.
Cenci G, Ciapponi L, Gatti M: The mechanism of telomere protection: a comparison between Drosophila and humans. Chromosoma 114:135–145 (2005).
16.
Chang M, Arneric M, Lingner J: Telomerase repeat addition processivity is increased at critically short telomeres in a Tel1-dependent manner in Saccharomyces cerevisiae. Genes Dev 21:2485–2494 (2007).
17.
Ciapponi L, Cenci G, Ducau J, Flores C, Johnson-Schlitz D, et al: The Drosophila Mre11/Rad50 complex is required to prevent both telomeric fusion and chromosome breakage. Curr Biol 14:1360–1366 (2004).
18.
Ciapponi L, Cenci G, Gatti M: The Drosophila Nbs protein functions in multiple pathways for the maintenance of genome stability. Genetics 173:1447–1454 (2006).
19.
Clerici M, Baldo V, Mantiero D, Lottersberger F, Lucchini G, Longhese MP: A Tel1/MRX-dependent checkpoint inhibits the metaphase-to-anaphase transition after UV irradiation in the absence of Mec1. Mol Cell Biol 24:10126–10144 (2004).
20.
Collura A, Blaisonneau J, Baldacci G, Francesconi S: The fission yeast Crb2/Chk1 pathway coordinates the DNA damage and spindle checkpoint in response to replication stress induced by topoisomerase I inhibitor. Mol Cell Biol 25:7889–7899 (2005).
21.
Cooper JP, Hiraoka Y: Fission yeast telomeres; in de Lange T, Lundblad V, Blackburn EH (eds): Telomeres, pp 495–523 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2006).
22.
Cooper JP, Nimmo ER, Allshire RC, Cech TR: Regulation of telomere length and function by a Myb-domain protein in fission yeast. Nature 385:744–747 (1997).
23.
Cristofari G, Lingner J: The telomerase ribonucleoprotein particle; in de Lange T, Lundblad V, Blackburn EH (eds): Telomeres, pp 21–47 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2006).
24.
d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, et al: A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198 (2003).
25.
D’Amours D, Jackson SP: The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3:317–327 (2002).
26.
de Lange T: Telomere dynamics and genome instability in human cancer; in de Lange T, Lundblad V, Blackburn EH (eds): Telomeres, pp 265–293 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1995).
27.
de Lange T: Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110 (2005).
28.
Denchi EL, de Lange T: Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448:1068–1071 (2007).
29.
Fanti L, Giovinazzo G, Berloco M, Pimpinelli S: The heterochromatin protein 1 prevents telomere fusions in Drosophila. Mol Cell 2:527–538 (1998).
30.
Fanti L, Berloco M, Piacentini L, Pimpinelli S: Chromosomal distribution of heterochromatin protein 1 (HP1) in Drosophila: a cytological map of euchromatic HP1 binding sites. Genetica 117:135–147 (2003).
31.
Ferreira MG, Cooper JP: Two modes of DNA double-strand break repair are reciprocally regulated through the fission yeast cell cycle. Genes Dev 18:2249–2254 (2004).
32.
Ferreira MG, Miller KM, Cooper JP: Indecent exposure: when telomeres become uncapped. Mol Cell 13:7–18 (2004).
33.
Frappart PO, McKinnon PJ: Ataxia-telangiectasia and related diseases. Neuromol Med 8:495–511 (2006).
34.
Gao H, Cervantes RB, Mandell EK, Otero JH, Lundblad V: RPA-like proteins mediate yeast telomere function. Nat Struct Mol Biol 14:208–214 (2007).
35.
Garber PM, Rine J: Overlapping roles of the spindle assembly and DNA damage checkpoints in the cell-cycle response to altered chromosomes in Saccharomyces cerevisiae. Genetics 161:521–534 (2002).
36.
Garcia-Cao M, O’Sullivan R, Peters AH, Jenuwein T, Blasco MA: Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 36:94–99 (2004).
37.
Garvik B, Carson M, Hartwell L: Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol Cell Biol 15:6128–6138 (1995).
38.
Gatti M, Baker BS: Genes controlling essential cell-cycle functions in Drosophila melanogaster. Genes Dev 3:438–453 (1989).
39.
Gatti M, Tanzarella C, Olivieri G: Analysis of the chromosome aberrations induced by X-rays in somatic cells of Drosophila melanogaster. Genetics 77:701–719 (1974).
40.
Gibson DG, Bell SP, Aparicio OM: Cell cycle execution point analysis of ORC function and characterization of the checkpoint response to ORC inactivation in Saccharomyces cerevisiae. Genes Cells 11:557–573 (2006).
41.
Gorski MM, Romeijn RJ, Eeken JC, De Jong AW, Van Veen BL, et al: Disruption of Drosophila Rad50 causes pupal lethality, the accumulation of DNA double-strand breaks and the induction of apoptosis in third instar larvae. DNA Repair (Amst) 3:603–615 (2004).
42.
Hande MP, Balajee AS, Tchirkov A, Wynshaw-Boris A, Lansdorp PM: Extra-chromosomal telomeric DNA in cells from Atm(–/–) mice and patients with ataxia-telangiectasia. Hum Mol Genet 10:519–528 (2001).
43.
Hari KL, Santerre A, Sekelsky JJ, McKim KS, Boyd JB, Hawley RS: The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell 82:815–821 (1995).
44.
Hastie ND, Allshire RC: Human telomeres: fusion and interstitial sites. Trends Genet 5:326–331 (1989).
45.
Hector RE, Shtofman RL, Ray A, Chen BR, Nyun T, et al: Tel1p preferentially associates with short telomeres to stimulate their elongation. Mol Cell 27:851–858 (2007).
46.
James TC, Eissenberg JC, Craig C, Dietrich V, Hobson A, Elgin SC: Distribution patterns of HP1, a heterochromatin-associated nonhistone chromosomal protein of Drosophila. Eur J Cell Biol 50:170–180 (1989).
47.
Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, et al: ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8:37–45 (2006).
48.
Kang J, Bronson RT, Xu Y: Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. EMBO J 21:1447–1455 (2002).
49.
Karess R: Rod-Zw10-Zwilch: a key player in the spindle checkpoint. Trends Cell Biol 15:386–392 (2005).
50.
Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T: p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283:1321–1325 (1999).
51.
Kim EM, Burke DJ: DNA damage activates the SAC in an ATM/ATR-dependent manner, independently of the kinetochore. PLoS Genet 4:e1000015 (2008).
52.
Koering CE, Pollice A, Zibella MP, Bauwens S, Puisieux A, et al: Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep 3:1055–1061 (2002).
53.
Longhese MP: DNA damage response at functional and dysfunctional telomeres. Genes Dev 22:125–140 (2008).
54.
Lundblad V: Budding yeast telomeres; in de Lange T, Lundblad V, Blackburn EH (eds): Telomeres, pp 345–386 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2006).
55.
Luo G, Yao MS, Bender CF, Mills M, Bladl AR, et al: Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 96:7376–7381 (1999).
56.
Maringele L, Lydall D: EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint pathways in budding yeast yku70Delta mutants. Genes Dev 16:1919–1933 (2002).
57.
Maser RS, DePinho RA: Connecting chromosomes, crisis, and cancer. Science 297:565–569 (2002).
58.
Mason JM, Biessmann H: The unusual telomeres of Drosophila. Trends Genet 11:58–62 (1995).
59.
Mason JM, Frydrychova RC, Biessmann H: Drosophila telomeres: an exception providing new insights. Bioessays 30:25–37 (2008).
60.
Mikhailov A, Cole RW, Rieder CL: DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint. Curr Biol 12:1797–1806 (2002).
61.
Miller KM, Cooper JP: The telomere protein Taz1 is required to prevent and repair genomic DNA breaks. Mol Cell 11:303–313 (2003).
62.
Musacchio A, Salmon ED: The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8:379–393 (2007).
63.
Musarò M, Ciapponi L, Fasulo B, Gatti M, Cenci G: Unprotected Drosophila melanogaster telomeres activate the spindle assembly checkpoint. Nat Genet 40:362–366 (2008).
64.
Nugent CI, Lundblad V: The telomerase reverse transcriptase: components and regulation. Genes Dev 12:1073–1085 (1998).
65.
Oikemus SR, McGinnis N, Queiroz-Machado J, Tukachinsky H, Takada S, et al: Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect. Genes Dev 18:1850–1861 (2004).
66.
Oikemus SR, Queiroz-Machado J, Lai K, McGinnis N, Sunkel C, Brodsky MH: Epigenetic telomere protection by Drosophila DNA damage response pathways. PLoS Genet 2:e71 (2006).
67.
Pandita TK: ATM function and telomere stability. Oncogene 21:611–618 (2002).
68.
Perrini B, Piacentini L, Fanti L, Altieri F, Chichiarelli S, et al: HP1 controls telomere capping, telomere elongation, and telomere silencing by two different mechanisms in Drosophila. Mol Cell 15:467–476 (2004).
69.
Pimpinelli S: Drosophila telomeres; in de Lange T, Lundblad V, Blackburn EH (eds): Telomeres, pp 433–463 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2006).
70.
Price C: Ciliate telomeres; in de Lange T, Lundblad V, Blackburn EH (eds): Telomeres, pp 465–493 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2006).
71.
Raffa GD, Cenci G, Siriaco G, Goldberg ML, Gatti M: The putative Drosophila transcription factor woc is required to prevent telomeric fusions. Mol Cell 20:821–831 (2005).
72.
Rong YS: Telomere capping in Drosophila: dealing with chromosome ends that most resemble DNA breaks. Chromosoma 117:235–242 (2008).
73.
Royou A, Macias H, Sullivan W: The Drosophila Grp/Chk1 DNA damage checkpoint controls entry into anaphase. Curr Biol 15:334–339 (2005).
74.
Sabourin M, Tuzon CT, Zakian VA: Telomerase and Tel1p preferentially associate with short telomeres in S. cerevisiae. Mol Cell 27:550–561 (2007).
75.
Shareef MM, King C, Damaj M, Badagu R, Huang DW, Kellum R: 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 (2001).
76.
Sharpless NE, DePinho RA: Telomeres, stem cells, senescence, and cancer. J Clin Invest 113:160–168 (2004).
77.
Shiloh Y: The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31:402–410 (2006).
78.
Silva E, Tiong S, Pedersen M, Homola EM, Royou A, et al: ATM is required for telomere maintenance and chromosome stability during Drosophila development. Curr Biol 14:1341–1347 (2004).
79.
Song YH, Mirey G, Betson M, Haber DA, Settleman J: The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development. Curr Biol 14:1354–1359 (2004).
80.
Stiff T, Reis C, Alderton GK, Woodbine L, O’Driscoll M, Jeggo PA: Nbs1 is required for ATR-dependent phosphorylation events. EMBO J 24:199–208 (2005).
81.
Sugimoto I, Murakami H, Tonami Y, Moriyama A, Nakanishi M: DNA replication checkpoint control mediated by the spindle checkpoint protein Mad2p in fission yeast. J Biol Chem 279:47372–47378 (2004).
82.
Takai H, Smogorzewska A, de Lange T: DNA damage foci at dysfunctional telomeres. Curr Biol 13:1549–1556 (2003).
83.
Theunissen JW, Kaplan MI, Hunt PA, Williams BR, Ferguson DO, et al: Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11 (ATLD1/ATLD1) mice. Mol Cell 12:1511–1523 (2003).
84.
van Steensel B, Smogorzewska A, de Lange T: TRF2 protects human telomeres from end-to-end fusions. Cell 92:401–413 (1998).
85.
Verdun RE, Karlseder J: The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127:709–720 (2006).
86.
Verdun RE, Crabbe L, Haggblom C, Karlseder J: Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell 20:551–561 (2005).
87.
Viscardi V, Bonetti D, Cartagena-Lirola H, Lucchini G, Longhese MP: MRX-dependent DNA damage response to short telomeres. Mol Biol Cell 18:3047–3058 (2007).
88.
Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, et al: Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421:643–648 (2003).
89.
Zachos G, Black EJ, Walker M, Scott MT, Vagnarelli P, et al: Chk1 is required for spindle checkpoint function. Dev Cell 12:247–260 (2007).
90.
Zhong H, Bryson A, Eckersdorff M, Ferguson DO: Rad50 depletion impacts upon ATR-dependent DNA damage responses. Hum Mol Genet 14:2685–2693 (2005).
91.
Zhu J, Petersen S, Tessarollo L, Nussenzweig A: Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr Biol 11:105–109 (2001).
92.
Zhu XD, Kuster B, Mann M, Petrini JH, Lange T: Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet 25:347–352 (2000).
93.
Zubko MK, Guillard S, Lydall D: Exo1 and Rad24 differentially regulate generation of ssDNA at telomeres of Saccharomyces cerevisiae cdc13-1 mutants. Genetics 168:103–115 (2004).
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