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The Analysis of () Mutants Reveals Differences in the Fusigenic Potential among Telomeres


Telomeres are specialized structures that protect chromosome ends from incomplete replication, degradation and end-to-end fusion. Abnormalities in telomere structure or maintenance can promote a variety of human diseases including premature aging and cancer. Although all human telomeres contain the same DNA sequences, they differ from each other in the subtelomeric regions or subtelomeres. Recent work has shown that human subtelomeres control telomere replication and that abnormalities in these structures can lead to localized chromosome instability and disease. However, the relationships between subtelomeres and telomeres are currently poorly understood. Here, we have addressed this problem using the fruit fly Drosophila melanogaster as model system. Drosophila subtelomers are very different from each other as they contain different types of chromatin. We have found that mutations in a gene we called pendolino (peo) cause telomeric fusions (TFs) and that these fusions preferentially involve the telomeres associated with a tightly packed form of chromatin called heterochromatin. Interestingly, none of the 10 mutants with TFs so far described in Drosophila shows the pattern of TFs observed in peo mutants. Thus, our data provide the first demonstration that subtelomeres can affect telomere fusion. We believe that these results will stimulate further studies on the role of subtelomeres in the maintenance of genome stability.


Vyšlo v časopise: The Analysis of () Mutants Reveals Differences in the Fusigenic Potential among Telomeres. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005260
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005260

Souhrn

Telomeres are specialized structures that protect chromosome ends from incomplete replication, degradation and end-to-end fusion. Abnormalities in telomere structure or maintenance can promote a variety of human diseases including premature aging and cancer. Although all human telomeres contain the same DNA sequences, they differ from each other in the subtelomeric regions or subtelomeres. Recent work has shown that human subtelomeres control telomere replication and that abnormalities in these structures can lead to localized chromosome instability and disease. However, the relationships between subtelomeres and telomeres are currently poorly understood. Here, we have addressed this problem using the fruit fly Drosophila melanogaster as model system. Drosophila subtelomers are very different from each other as they contain different types of chromatin. We have found that mutations in a gene we called pendolino (peo) cause telomeric fusions (TFs) and that these fusions preferentially involve the telomeres associated with a tightly packed form of chromatin called heterochromatin. Interestingly, none of the 10 mutants with TFs so far described in Drosophila shows the pattern of TFs observed in peo mutants. Thus, our data provide the first demonstration that subtelomeres can affect telomere fusion. We believe that these results will stimulate further studies on the role of subtelomeres in the maintenance of genome stability.


Zdroje

1. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annual Review of Genetics. 2008;42:301–34. doi: 10.1146/annurev.genet.41.110306.130350 18680434

2. O'Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nature reviews Molecular Cell Biology. 2010;11:171–81. doi: 10.1038/nrm2848 20125188

3. Jain D, Cooper JP. Telomeric strategies: means to an end. Annual Review of Genetics. 2010;44:243–69. doi: 10.1146/annurev-genet-102108-134841 21047259

4. Stewart JA, Chaiken MF, Wang F, Price CM. Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation. Mutation Research. 2012;730:12–9. doi: 10.1016/j.mrfmmm.2011.08.011 21945241

5. Mason JM, Frydrychova RC, Biessmann H. Drosophila telomeres: an exception providing new insights. BioEssays. 2008;30:25–37. 18081009

6. Raffa GD, Cenci G, Ciapponi L, Gatti M. Organization and Evolution of Drosophila Terminin: Similarities and Differences between Drosophila and Human Telomeres. Frontiers in Oncology. 2013;3:112. doi: 10.3389/fonc.2013.00112 23675571

7. Rong YS. Telomere capping in Drosophila: dealing with chromosome ends that most resemble DNA breaks. Chromosoma. 2008;117:235–42. doi: 10.1007/s00412-007-0144-2 18193446

8. Leman AR, Dheekollu J, Deng Z, Lee SW, Das MM, Lieberman PM, et al. Timeless preserves telomere length by promoting efficient DNA replication through human telomeres. Cell Cycle. 2012;11:2337–47. doi: 10.4161/cc.20810 22672906

9. Vannier JB, Pavicic-Kaltenbrunner V, Petalcorin MI, Ding H, Boulton SJ. RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell. 2012;149:795–806. doi: 10.1016/j.cell.2012.03.030 22579284

10. Cenci G, Rawson RB, Belloni G, Castrillon DH, Tudor M, Petrucci R, et al. UbcD1, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior. Genes Dev. 1997;11:863–75. 9106658

11. Cipressa F, Romano S, Centonze S, Zur Lage PI, Verni F, Dimitri P, et al. Effete, a Drosophila Chromatin-Associated Ubiquitin-Conjugating Enzyme that Affects Telomeric and Heterochromatic Position Effect Variegation. Genetics. 2013;195:147–58 doi: 10.1534/genetics.113.153320 23821599

12. Fanti L, Giovinazzo G, Berloco M, Pimpinelli S. The heterochromatin protein 1 prevents telomere fusions in Drosophila. Mol Cell. 1998;2:527–38. 9844626

13. Bi X, Srikanta D, Fanti L, Pimpinelli S, Badugu R, Kellum R, et al. Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance. Proc Natl Acad Sci U S A. 2005;102:15167–72. 16203987

14. Bi X, Wei SC, Rong YS. Telomere protection without a telomerase; the role of ATM and Mre11 in Drosophila telomere maintenance. Curr Biol. 2004;14:1348–53. 15296751

15. Ciapponi L, Cenci G, Ducau J, Flores C, Johnson-Schlitz D, Gorski MM, et al. The Drosophila Mre11/Rad50 complex is required to prevent both telomeric fusion and chromosome breakage. Curr Biol. 2004;14:1360–6. 15296753

16. Ciapponi L, Cenci G, Gatti M. The Drosophila Nbs protein functions in multiple pathways for the maintenance of genome stability. Genetics. 2006. 173:1447–54 16648644

17. Oikemus SR, McGinnis N, Queiroz-Machado J, Tukachinsky H, Takada S, Sunkel CE, et al. Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect. Genes Dev. 2004;18:1850–61. 15256487

18. Oikemus SR, Queiroz-Machado J, Lai K, McGinnis N, Sunkel C, Brodsky MH. Epigenetic telomere protection by Drosophila DNA damage response pathways. PLoS Genet. 2006;2:e71. 16710445

19. Silva E, Tiong S, Pedersen M, Homola E, Royou A, Fasulo B, et al. ATM is required for telomere maintenance and chromosome stability during Drosophila development. Curr Biol. 2004;14:1341–7. 15296750

20. Raffa GD, Cenci G, Siriaco G, Goldberg ML, Gatti M. The putative Drosophila transcription factor woc is required to prevent telomeric fusions. Mol Cell. 2005;20:821–31. 16364909

21. Cenci G, Siriaco G, Raffa GD, Kellum R, Gatti M. The Drosophila HOAP protein is required for telomere capping. Nat Cell Biol. 2003;5:82–4. 12510197

22. Gao G, Walser JC, Beaucher ML, Morciano P, Wesolowska N, Chen J, et al. HipHop interacts with HOAP and HP1 to protect Drosophila telomeres in a sequence-independent manner. The EMBO Journal. 2010;29:819–29. doi: 10.1038/emboj.2009.394 20057353

23. Raffa GD, Raimondo D, Sorino C, Cugusi S, Cenci G, Cacchione S, et al. Verrocchio, a Drosophila OB fold-containing protein, is a component of the terminin telomere-capping complex. Genes Dev. 2010;24:1596–601. doi: 10.1101/gad.574810 20679394

24. Raffa GD, Siriaco G, Cugusi S, Ciapponi L, Cenci G, Wojcik E, et al. The Drosophila modigliani (moi) gene encodes a HOAP-interacting protein required for telomere protection. Proc Natl Acad Sci U S A. 2009;106:2271–6. doi: 10.1073/pnas.0812702106 19181850

25. Raffa GD, Ciapponi L, Cenci G, Gatti M. Terminin: a protein complex that mediates epigenetic maintenance of Drosophila telomeres. Nucleus. 2011;2:383–91. doi: http://dx.doi.org/10.4161/nucl.2.5.17873 21989238

26. 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. 2001;12:1671–85. 11408576

27. Drosopoulos WC, Kosiyatrakul ST, Yan Z, Calderano SG, Schildkraut CL. Human telomeres replicate using chromosome-specific, rather than universal, replication programs. The Journal of Cell Biology. 2012;197:253–66. doi: 10.1083/jcb.201112083 22508510

28. Arnoult N, Schluth-Bolard C, Letessier A, Drascovic I, Bouarich-Bourimi R, Campisi J, et al. Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization. PLoS Genet. 2010;6:e1000920. doi: 10.1371/journal.pgen.1000920 20421929

29. Novo C, Arnoult N, Bordes WY, Castro-Vega L, Gibaud A, Dutrillaux B, et al. The heterochromatic chromosome caps in great apes impact telomere metabolism. Nucleic acids research. 2013;41:4792–801. doi: 10.1093/nar/gkt169 23519615

30. O'Brien MA, Roberts MS, Taghert PH. A genetic and molecular analysis of the 46C chromosomal region surrounding the FMRFamide neuropeptide gene in Drosophila melanogaster. Genetics. 1994;137:121–37. 8056304

31. Levis R, Hazelrigg T, Rubin GM. Separable cis-acting control elements for expression of the white gene of Drosophila. The EMBO Journal. 1985;4:3489–99. 3004962

32. Castrillon DH, Gonczy P, Alexander S, Rawson R, Eberhart CG, Viswanathan S, et al. Toward a molecular genetic analysis of spermatogenesis in Drosophila melanogaster: characterization of male-sterile mutants generated by single P element mutagenesis. Genetics. 1993;135:489–505. 8244010

33. Fabrizio JJ, Hime G, Lemmon SK, Bazinet C. Genetic dissection of sperm individualization in Drosophila melanogaster. Development. 1998;125:1833–43. 9550716

34. van Wijk SJ, Timmers HT. The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins. FASEB Journal. 2010;24:981–93. doi: 10.1096/fj.09-136259 19940261

35. de Lange T. Protection of mammalian telomeres. Oncogene. 2002;21:532–40. 11850778

36. Csink AK, Henikoff S. Large-scale chromosomal movements during interphase progression in Drosophila. The Journal of Cell Biology. 1998;143:13–22. 9763417

37. Konishi A, de Lange T. Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2. Genes Dev. 2008;22:1221–30. doi: 10.1101/gad.1634008 18451109

38. Gatti M, Pimpinelli S. Functional elements in Drosophila melanogaster heterochromatin. Annual Review of Genetics. 1992;26:239–75. 1482113

39. Lindsley DL, Zimm GG. The Genome of Drosophila melanogaster. 1250 Sixth Avenue, San Diego, California 92101–4311: Academic Press, Inc.; 1992.

40. Ye Y, Rape M. Building ubiquitin chains: E2 enzymes at work. Nature Reviews Molecular Cell biology. 2009;10:755–64. doi: 10.1038/nrm2780 19851334

41. Cottee PA, Abs ELOYG, Nisbet AJ, Gasser RB. Ubiquitin-conjugating enzyme genes in Oesophagostomum dentatum. Parasitology Research. 2006;99:119–25. 16518612

42. Fanti L, Pimpinelli S. HP1: a functionally multifaceted protein. Current opinion in genetics & development. 2008;18:169–74.

43. Burla R, Carcuro M, Raffa GD, Galati A, Raimondo D, Rizzo A, et al. AKTIP/Ft1, a new shelterin-interacting factor required for telomere maintenance. PLoS Genet. 2015; 11:e1005167. doi: 10.1371/journal.pgen.1005167

44. Chagin VO, Stear JH, Cardoso MC. Organization of DNA replication. Cold Spring Harbor perspectives in biology. 2010;2:a000737. doi: 10.1101/cshperspect.a000737 20452942

45. Ghosh AK, Rossi ML, Singh DK, Dunn C, Ramamoorthy M, Croteau DL, et al. RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. The Journal of Biological Chemistry. 2012;287:196–209. doi: 10.1074/jbc.M111.295063 22039056

46. Barefield C, Karlseder J. The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures. Nucleic Acids Research. 2012;40:7358–67. doi: 10.1093/nar/gks407 22576367

47. Sfeir A, Kosiyatrakul ST, Hockemeyer D, MacRae SL, Karlseder J, Schildkraut CL, et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell. 2009;138:90–103. doi: 10.1016/j.cell.2009.06.021 19596237

48. Benna C, Bonaccorsi S, Wulbeck C, Helfrich-Forster C, Gatti M, Kyriacou CP, et al. Drosophila timeless2 is required for chromosome stability and circadian photoreception. Curr Biol. 2010;20:346–52. doi: 10.1016/j.cub.2009.12.048 20153199

49. Gotter AL, Suppa C, Emanuel BS. Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. Journal of Molecular Biology. 2007;366:36–52. 17141802

50. Kondratov RV, Antoch MP. Circadian proteins in the regulation of cell cycle and genotoxic stress responses. Trends in Cell Biology. 2007;17:311–7. 17644383

51. Kusano K, Johnson-Schlitz DM, Engels WR. Sterility of Drosophila with mutations in the Bloom syndrome gene—complementation by Ku70. Science. 2001;291:2600–2. 11283371

52. Pardue ML, Debaryshe P. Adapting to life at the end of the line: How Drosophila telomeric retrotransposons cope with their job. Mobile Genetic Elements. 2011;1:128–34. 22016861

53. Zhang L, Rong YS. Retrotransposons at Drosophila telomeres: host domestication of a selfish element for the maintenance of genome integrity. Biochimica et Biophysica Acta. 2012;1819:771–5. doi: 10.1016/j.bbagrm.2012.01.018 22342531

54. Hoskins RA, Carlson JW, Kennedy C, Acevedo D, Evans-Holm M, Frise E, et al. Sequence finishing and mapping of Drosophila melanogaster heterochromatin. Science. 2007;316:1625–8. 17569867

55. Mason J, Villasante A. Subtelomeres in Drosophila and Other Diptera. In: Louis EJ, Becker MM, editors. Subtelomeres: Springer Berlin Heidelberg; 2014. p. 211–25.

56. Riddle NC, Shaffer CD, Elgin SC. A lot about a little dot—lessons learned from Drosophila melanogaster chromosome 4. Biochemistry and Cell Biology. 2009;87:229–41. doi: 10.1139/O08-119 19234537

57. Biessmann H, Prasad S, Semeshin VF, Andreyeva EN, Nguyen Q, Walter MF, et al. Two distinct domains in Drosophila melanogaster telomeres. Genetics. 2005;171:1767–77. 16143601

58. Wang SH, Nan R, Accardo MC, Sentmanat M, Dimitri P, Elgin SC. A distinct type of heterochromatin at the telomeric region of the Drosophila melanogaster Y chromosome. PLoS One. 2014;9:e86451. doi: 10.1371/journal.pone.0086451 24475122

59. Weiler KS, Wakimoto BT. Heterochromatin and gene expression in Drosophila. Annual Review of Genetics. 1995;29:577–605. 8825487

60. Elgin SC, Reuter G. Position-effect variegation, heterochromatin formation, and gene silencing in Drosophila. Cold Spring Harbor Perspectives in Biology. 2013;5:a017780. doi: 10.1101/cshperspect.a017780 23906716

61. Gatti M, Baker BS. Genes controlling essential cell-cycle functions in Drosophila melanogaster. Genes Dev. 1989;3:438–53. 2498166

62. Loupart ML, Krause SA, Heck MS. Aberrant replication timing induces defective chromosome condensation in Drosophila ORC2 mutants. Curr Biol. 2000;10:1547–56. 11137005

63. Somma MP, Ceprani F, Bucciarelli E, Naim V, De Arcangelis V, Piergentili R, et al. Identification of Drosophila mitotic genes by combining co-expression analysis and RNA interference. PLoS Genet. 2008;4:e1000126. doi: 10.1371/journal.pgen.1000126 18797514

64. Balasov M, Huijbregts RP, Chesnokov I. Functional analysis of an Orc6 mutant in Drosophila. Proc Natl Acad Sci U S A. 2009;106:10672–7. doi: 10.1073/pnas.0902670106 19541634

65. Wallace JA, Orr-Weaver TL. Replication of heterochromatin: insights into mechanisms of epigenetic inheritance. Chromosoma. 2005;114:389–402. 16220346

66. Martinez P, Thanasoula M, Munoz P, Liao C, Tejera A, McNees C, et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23:2060–75. doi: 10.1101/gad.543509 19679647

67. Dimitri P, Arca B, Berghella L, Mei E. High genetic instability of heterochromatin after transposition of the LINE-like I factor in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1997;94:8052–7. 9223313

68. Koundakjian EJ, Cowan DM, Hardy RW, Becker AH. The Zuker collection: a resource for the analysis of autosomal gene function in Drosophila melanogaster. Genetics. 2004;167:203–6. 15166147

69. Lattao R, Bonaccorsi S, Guan X, Wasserman SA, Gatti M. Tubby-tagged balancers for the Drosophila X and second chromosomes. Fly. 2011;5:369–70. doi: 10.4161/fly.5.4.17283 21785267

70. Bonaccorsi S, Giansanti MG, Gatti M. Spindle assembly in Drosophila neuroblasts and ganglion mother cells. Nat Cell Biol. 2000;2:54–6. 10620808

71. Giansanti MG, Bonaccorsi S, Kurek R, Farkas RM, Dimitri P, Fuller MT, et al. The class I PITP giotto is required for Drosophila cytokinesis. Curr Biol. 2006;16:195–201. 16431372

72. Biegert A, Soding J. Sequence context-specific profiles for homology searching. Proc Natl Acad Sci U S A. 2009;106:3770–5. doi: 10.1073/pnas.0810767106 19234132

73. Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, et al. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Research. 2003;31:3497–500. 12824352

74. Soding J, Biegert A, Lupas AN. The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Research. 2005;33 (Web Server issue):W244–8. 15980461

75. Biegert A, Mayer C, Remmert M, Soding J, Lupas AN. The MPI Bioinformatics Toolkit for protein sequence analysis. Nucleic Acids Research. 2006;34 (Web Server issue):W335–9. 16845021

76. Roy A, Kucukural A, Zhang Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nature Protocols. 2010;5:725–38. doi: 10.1038/nprot.2010.5 20360767

77. Li Y, Roy A, Zhang Y. HAAD: A quick algorithm for accurate prediction of hydrogen atoms in protein structures. PloS One. 2009;4:e6701. doi: 10.1371/journal.pone.0006701 19693270

78. Zhang J, Liang Y, Zhang Y. Atomic-level protein structure refinement using fragment-guided molecular dynamics conformation sampling. Structure. 2011;19:1784–95. doi: 10.1016/j.str.2011.09.022 22153501

79. Wallner B, Elofsson A. Identification of correct regions in protein models using structural, alignment, and consensus information. Protein Science. 2006;15:900–13. 16522791

80. Benkert P, Biasini M, Schwede T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics. 2011;27:343–50. doi: 10.1093/bioinformatics/btq662 21134891

81. Abad JP, De Pablos B, Osoegawa K, De Jong PJ, Martin-Gallardo A, Villasante A. Genomic analysis of Drosophila melanogaster telomeres: full-length copies of HeT-A and TART elements at telomeres. Molecular Biology and Evolution. 2004;21:1613–9. 15163766

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