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  • Perspective
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Telomeric circles: universal players in telomere maintenance?

Nature Structural & Molecular Biology volume 16, pages 1010–1015 (2009)Cite this article

Abstract

To maintain linear DNA genomes, organisms have evolved numerous means of solving problems associated with DNA ends (telomeres), including telomere-associated retrotransposons, palindromes, hairpins, covalently bound proteins and the addition of arrays of simple DNA repeats. Telomeric arrays can be maintained through various mechanisms such as telomerase activity or recombination. The recombination-dependent maintenance pathways may include telomeric loops (t-loops) and telomeric circles (t-circles). The potential involvement of t-circles in telomere maintenance was first proposed for linear mitochondrial genomes. The occurrence of t-circles in a wide range of organisms, spanning yeasts, plants and animals, suggests the involvement of t-circles in many phenomena including the alternative-lengthening of telomeres (ALT) pathway and telomere rapid deletion (TRD). In this Perspective, we summarize these findings and discuss how t-circles may be related to t-loops and how t-circles may have initiated the evolution of telomeres.

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Figure 1: t-circles and t-loops seem to be common players in telomere maintenance.
Figure 2: Evolutionary scenario for the emergence of linear chromosomes terminating with t-arrays and hypotheses on the emergence of t-circles.

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References

  1. Gilson, E. & Géli, V. How telomeres are replicated. Nat. Rev. Mol. Cell Biol. 8, 825–838 (2007).

    Article  CAS  Google Scholar 

  2. McEachern, M.J., Krauskopf, A. & Blackburn, E.H. Telomeres and their control. Annu. Rev. Genet. 34, 331–358 (2000).

    Article  CAS  Google Scholar 

  3. Verdun, R.E. & Karlseder, J. Replication and protection of telomeres. Nature 447, 924–931 (2007).

    Article  CAS  Google Scholar 

  4. Nosek, J., Kosa, P. & Tomaska, L. On the origin of telomeres: a glimpse at the pre-telomerase world. Bioessays 28, 182–190 (2006).

    Article  CAS  Google Scholar 

  5. Pardue, M.L. & DeBaryshe, P.G. Drosophila telomeres: a variation on the telomerase theme. in Origin and Evolution of Telomeres (eds. Nosek, J. & Tomaska, L.) 27–44 (Landes Bioscience, Austin, Texas, 2008).

    Google Scholar 

  6. Pich, U., Fuchs, J. & Schubert, I. How do Alliaceae stabilize their chromosome ends in the absence of TTTAGGG sequences? Chromosome Res. 4, 207–213 (1996).

    Article  CAS  Google Scholar 

  7. Nosek, J. & Tomaska, L. Mitochondrial telomeres: an evolutionary paradigm for the emergence of telomeric structures and their replication strategies. in Origin and Evolution of Telomeres (eds. Nosek, J. & Tomaska, L.) 163–171 (Landes Bioscience, Austin, Texas, 2008).

    Chapter  Google Scholar 

  8. Tomaska, L., McEachern, M.J. & Nosek, J. Alternatives to telomerase: keeping linear chromosomes via telomeric circles. FEBS Lett. 567, 142–146 (2004).

    Article  CAS  Google Scholar 

  9. Blackburn, E.H. Telomere states and cell fates. Nature 408, 53–56 (2000).

    Article  CAS  Google Scholar 

  10. de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Cesare, A.J. & Reddel, R.R. Telomere uncapping and alternative lengthening of telomeres. Mech. Ageing Dev. 129, 99–108 (2008).

    Article  CAS  Google Scholar 

  13. Cesare, A.J. & Reddel, R.R. Alternative lengthening of telomeres in mammalian cells. in Origin and Evolution of Telomeres (eds. Nosek, J. & Tomaska, L.) 45–57 (Landes Bioscience, Austin, Texas, 2008).

    Google Scholar 

  14. Lundblad, V. Telomere maintenance without telomerase. Oncogene 21, 522–531 (2002).

    Article  CAS  Google Scholar 

  15. Lundblad, V. & Blackburn, E.H. An alternative pathway for yeast telomere maintenance rescues est1− senescence. Cell 73, 347–360 (1993).

    Article  CAS  Google Scholar 

  16. Teng, S.C. & Zakian, V.A. Telomere-telomere recombination is an efficient bypass pathway for telomere maintenance in Saccharomyces cerevisiae. Mol. Cell. Biol. 19, 8083–8093 (1999).

    Article  CAS  Google Scholar 

  17. Kovac, L., Lazowska, J. & Slonimski, P.P. A yeast with linear molecules of mitochondrial DNA. Mol. Gen. Genet. 197, 420–424 (1984).

    Article  CAS  Google Scholar 

  18. Nosek, J., Dinouel, N., Kovac, L. & Fukuhara, H. Linear mitochondrial DNAs from yeasts: telomeres with large tandem repetitions. Mol. Gen. Genet. 247, 61–72 (1995).

    Article  CAS  Google Scholar 

  19. Tomaska, L., Nosek, J. & Fukuhara, H. Identification of a putative mitochondrial telomere-binding protein of the yeast Candida parapsilosis. J. Biol. Chem. 272, 3049–3056 (1997).

    Article  CAS  Google Scholar 

  20. Nosek, J., Tomaska, L., Pagacova, B. & Fukuhara, H. Mitochondrial telomere-binding protein from Candida parapsilosis suggests an evolutionary adaptation of a nonspecific single-stranded DNA-binding protein. J. Biol. Chem. 274, 8850–8857 (1999).

    Article  CAS  Google Scholar 

  21. Tomaska, L., Makhov, A.M., Nosek, J., Kucejova, B. & Griffith, J.D. Electron microscopic analysis supports a dual role for the mitochondrial telomere-binding protein of Candida parapsilosis. J. Mol. Biol. 305, 61–69 (2001).

    Article  CAS  Google Scholar 

  22. Tomaska, L., Nosek, J. & Kucejova, B. Mitochondrial single-stranded DNA-binding proteins: in search for new functions. Biol. Chem. 382, 179–186 (2001).

    CAS  PubMed  Google Scholar 

  23. Tomaska, L., Nosek, J., Makhov, A.M., Pastorakova, A. & Griffith, J.D. Extragenomic double-stranded DNA circles in yeast with linear mitochondrial genomes: potential involvement in telomere maintenance. Nucleic Acids Res. 28, 4479–4487 (2000).

    Article  CAS  Google Scholar 

  24. Nosek, J., Rycovska, A., Makhov, A.M., Griffith, J.D. & Tomaska, L. Amplification of telomeric arrays via rolling-circle mechanism. J. Biol. Chem. 280, 10840–10845 (2005).

    Article  CAS  Google Scholar 

  25. Kosa, P., Valach, M., Tomaska, L., Wolfe, K.H. & Nosek, J. Complete DNA sequences of the mitochondrial genomes of the pathogenic yeasts Candida orthopsilosis and Candida metapsilosis: insight into the evolution of linear DNA genomes from mitochondrial telomere mutants. Nucleic Acids Res. 34, 2472–2481 (2006).

    Article  CAS  Google Scholar 

  26. Rycovska, A., Valach, M., Tomaska, L., Bolotin-Fukuhara, M. & Nosek, J. Linear versus circular mitochondrial genomes: intraspecies variability of mitochondrial genome architecture in Candida parapsilosis. Microbiology 150, 1571–1580 (2004).

    Article  CAS  Google Scholar 

  27. Cohen, S., Regev, A. & Lavi, S. Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability. Oncogene 14, 977–985 (1997).

    Article  CAS  Google Scholar 

  28. Ogino, H. et al. Release of telomeric DNA from chromosomes in immortal human cells lacking telomerase activity. Biochem. Biophys. Res. Commun. 248, 223–227 (1998).

    Article  CAS  Google Scholar 

  29. Regev, A., Cohen, S., Cohen, E., Bar-Am, I. & Lavi, S. Telomeric repeats on small polydisperse circular DNA (spcDNA) and genomic instability. Oncogene 17, 3455–3461 (1998).

    Article  CAS  Google Scholar 

  30. Tokutake, Y. et al. Extra-chromosomal telomere repeat DNA in telomerase-negative immortalized cell lines. Biochem. Biophys. Res. Commun. 247, 765–772 (1998).

    Article  CAS  Google Scholar 

  31. Cesare, A.J., Groff-Vindman, C., Compton, S.A., McEachern, M.J. & Griffith, J.D. Telomere loops and homologous recombination-dependent telomeric circles in a Kluyveromyces lactis telomere mutant strain. Mol. Cell. Biol. 28, 20–29 (2008).

    Article  CAS  Google Scholar 

  32. Groff-Vindman, C., Cesare, A.J., Natarajan, S., Griffith, J.D. & McEachern, M.J. Recombination at long mutant telomeres produces tiny single- and double-stranded telomeric circles. Mol. Cell. Biol. 25, 4406–4412 (2005).

    Article  CAS  Google Scholar 

  33. Raices, M. et al. C. elegans telomeres contain G-strand and C-strand overhangs that are bound by distinct proteins. Cell 132, 745–757 (2008).

    Article  CAS  Google Scholar 

  34. Zellinger, B., Akimcheva, S., Puizina, J., Schirato, M. & Riha, K. Ku suppresses formation of telomeric circles and alternative telomere lengthening in Arabidopsis. Mol. Cell 27, 163–169 (2007).

    Article  CAS  Google Scholar 

  35. Cohen, S. & Méchali, M. Formation of extrachromosomal circles from telomeric DNA in Xenopus laevis. EMBO Rep. 3, 1168–1174 (2002).

    Article  CAS  Google Scholar 

  36. Cesare, A.J. & Griffith, J.D. Telomeric DNA in ALT cells is characterized by free telomeric circles and heterogeneous t-loops. Mol. Cell. Biol. 24, 9948–9957 (2004).

    Article  CAS  Google Scholar 

  37. Nabetani, A. & Ishikawa, F. Unusual telomeric DNAs in human telomerase-negative immortalized cells. Mol. Cell. Biol. 29, 703–713 (2009).

    Article  CAS  Google Scholar 

  38. Wang, R.C., Smogorzewska, A. & de Lange, T. Homologous recombination generates t-loop-sized deletions at human telomeres. Cell 119, 355–368 (2004).

    Article  CAS  Google Scholar 

  39. Wang, Y., Ghosh, G. & Hendrickson, E.A. Ku86 represses lethal telomere deletion events in human somatic cells. Proc. Natl. Acad. Sci. USA 106, 12430–12435 (2009).

    Article  CAS  Google Scholar 

  40. Pickett, H.A., Cesare, A.J., Johnston, R.L., Neumann, A.A. & Reddel, R.R. Control of telomere length by a trimming mechanism that involves generation of t-circles. EMBO J. 28, 799–809 (2009).

    Article  CAS  Google Scholar 

  41. Liu, L. et al. Telomere lengthening early in development. Nat. Cell Biol. 9, 1436–1441 (2007).

    Article  CAS  Google Scholar 

  42. Topcu, Z., Nickles, K., Davis, C. & McEachern, M.J. Abrupt disruption of capping and a single source for recombinationally elongated telomeres in Kluyveromyces lactis. Proc. Natl. Acad. Sci. USA 102, 3348–3353 (2005).

    Article  CAS  Google Scholar 

  43. Natarajan, S., Groff-Vindman, C. & McEachern, M.J. Factors influencing the recombinational expansion and spread of telomeric tandem arrays in Kluyveromyces lactis. Eukaryot. Cell 2, 1115–1127 (2003).

    Article  CAS  Google Scholar 

  44. Natarajan, S. & McEachern, M.J. Recombinational telomere elongation promoted by DNA circles. Mol. Cell. Biol. 22, 4512–4521 (2002).

    Article  CAS  Google Scholar 

  45. Tomaska, L. & Nosek, J. Telomere heterogeneity: taking advantage of stochastic events. FEBS Lett. 583, 1067–1071 (2009).

    Article  CAS  Google Scholar 

  46. Lustig, A.J. Clues to catastrophic telomere loss in mammals from yeast telomere rapid deletion. Nat. Rev. Genet. 4, 916–923 (2003).

    Article  CAS  Google Scholar 

  47. Cerone, M.A., Londono-Vallejo, J.A. & Bacchetti, S. Telomere maintenance by telomerase and by recombination can coexist in human cells. Hum. Mol. Genet. 10, 1945–1952 (2001).

    Article  CAS  Google Scholar 

  48. Deng, Z., Dheekollu, J., Broccoli, D., Dutta, A. & Lieberman, P.M. The origin recognition complex localizes to telomere repeats and prevents telomere-circle formation. Curr. Biol. 17, 1989–1995 (2007).

    Article  CAS  Google Scholar 

  49. Li, B., Jog, S.P., Reddy, S. & Comai, L. WRN controls formation of extrachromosomal telomeric circles and is required for TRF2ΔB-mediated telomere shortening. Mol. Cell. Biol. 28, 1892–1904 (2008).

    Article  Google Scholar 

  50. Compton, S.A., Choi, J.H., Cesare, A.J., Ozgur, S. & Griffith, J.D. Xrcc3 and Nbs1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells. Cancer Res. 67, 1513–1519 (2007).

    Article  CAS  Google Scholar 

  51. Zhong, Z.H. et al. Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres. J. Biol. Chem. 282, 29314–29322 (2007).

    Article  CAS  Google Scholar 

  52. Cerone, M.A., Autexier, C., Londono-Vallejo, J.A. & Bacchetti, S. A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT. Oncogene 24, 7893–7901 (2005).

    Article  CAS  Google Scholar 

  53. Jiang, W.Q. et al. Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex. Mol. Cell. Biol. 25, 2708–2721 (2005).

    Article  CAS  Google Scholar 

  54. Muntoni, A. & Reddel, R.R. The first molecular details of ALT in human tumor cells. Hum. Mol. Genet. 14, R191–R196 (2005).

    Article  CAS  Google Scholar 

  55. Compton, S.A., Tolun, G., Kamath-Loeb, A.S., Loeb, L.A. & Griffith, J.D. The Werner syndrome protein binds replication fork and holliday junction DNAs as an oligomer. J. Biol. Chem. 283, 24478–24483 (2008).

    Article  CAS  Google Scholar 

  56. Poulet, A. et al. TRF2 promotes, remodels and protects telomeric Holliday junctions. EMBO J. 28, 641–651 (2009).

    Article  CAS  Google Scholar 

  57. Fouché, N. et al. The basic domain of TRF2 directs binding to DNA junctions irrespective of the presence of TTAGGG repeats. J. Biol. Chem. 281, 37486–37495 (2006).

    Article  Google Scholar 

  58. Palm, W. & de Lange, T. How shelterin protects mammalian telomeres. Annu. Rev. Genet. 42, 301–334 (2008).

    Article  CAS  Google Scholar 

  59. de Lange, T. T-loops and the origin of telomeres. Nat. Rev. Mol. Cell Biol. 5, 323–329 (2004).

    Article  CAS  Google Scholar 

  60. Blanc, H. & Dujon, B. Replicator regions of the yeast mitochondrial DNA responsible for suppressiveness. Proc. Natl. Acad. Sci. USA 77, 3942–3946 (1980).

    Article  CAS  Google Scholar 

  61. MacAlpine, D.M., Kolesar, J., Okamoto, K., Butow, R.A. & Perlman, P.S. Replication and preferential inheritance of hypersuppressive petite mitochondrial DNA. EMBO J. 20, 1807–1817 (2001).

    Article  CAS  Google Scholar 

  62. Bibillo, A. & Eickbush, T.H. End-to-end template jumping by the reverse transcriptase encoded by the R2 retrotransposon. J. Biol. Chem. 279, 14945–14953 (2004).

    Article  CAS  Google Scholar 

  63. Chen, B. & Lambowitz, A.M. De novo and DNA primer-mediated initiation of cDNA synthesis by the mauriceville retroplasmid reverse transcriptase involve recognition of a 3′ CCA sequence. J. Mol. Biol. 271, 311–332 (1997).

    Article  CAS  Google Scholar 

  64. Kennell, J.C., Wang, H. & Lambowitz, A.M. The Mauriceville plasmid of Neurospora spp. uses novel mechanisms for initiating reverse transcription in vivo. Mol. Cell. Biol. 14, 3094–3107 (1994).

    Article  CAS  Google Scholar 

  65. Azzalin, C.M., Reichenbach, P., Khoriauli, L., Giulotto, E. & Lingner, J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318, 798–801 (2007).

    Article  CAS  Google Scholar 

  66. Schoeftner, S. & Blasco, M.A. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat. Cell Biol. 10, 228–236 (2008).

    Article  CAS  Google Scholar 

  67. Nosek, J. et al. Complete DNA sequence of the linear mitochondrial genome of the pathogenic yeast Candida parapsilosis. Mol. Genet. Genomics 272, 173–180 (2004).

    Article  CAS  Google Scholar 

  68. Tomaska, L., Makhov, A.M., Griffith, J.D. & Nosek, J. t-loops in yeast mitochondria. Mitochondrion 1, 455–459 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We wish to thank L. Kovac (Comenius University) for inspiration and continuous support and members of our laboratories for discussions. We also thank two anonymous reviewers for valuable comments and suggestions. Our work related to telomere biology is supported by grants from a Fogarty International Research Collaboration Award (2-R03-TW005654-04A1), the Howard Hughes Medical Institute (55005622), the Slovak grant agencies APVT (20-001604 and 0024-07) and VEGA (1/0132/09 and 1/0219/08), and grants to J.D.G. (US National Institutes of Health grants GM31819 and ES13773 and awards from the Ellison and Glenn foundations).

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  1. Departments of Genetics and Biochemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Bratislava, Slovakia

    Lubomir Tomaska, Jozef Nosek & Juraj Kramara

  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Jack D Griffith

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Correspondence to Lubomir Tomaska or Jack D Griffith.

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Tomaska, L., Nosek, J., Kramara, J. et al. Telomeric circles: universal players in telomere maintenance?. Nat Struct Mol Biol 16, 1010–1015 (2009). https://doi.org/10.1038/nsmb.1660

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