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Long telomeres are preferentially extended during recombination-mediated telomere maintenance

Nature Structural & Molecular Biology volume 18, pages 451–456 (2011)Cite this article

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Abstract

Most human somatic cells do not express telomerase. Consequently, with each cell division their telomeres progressively shorten until replicative senescence is induced. Around 15% of human cancers maintain their telomeres using telomerase-independent, recombination-based mechanisms that are collectively termed 'alternative lengthening of telomeres' (ALT). In the yeast Saccharomyces cerevisiae, ALT cells are referred to as 'survivors'. One type of survivor (type II) resembles human ALT cells in that both are defined by the amplification of telomeric repeats. We analyzed recombination-mediated telomere extension events at individual telomeres in telomerase-negative yeast during the formation of type II survivors and found that long telomeres were preferentially extended. Furthermore, senescent cells with long telomeres were more efficient at bypassing senescence by the type II pathway. We speculate that telomere length may be important in determining whether cancer cells use telomerase or ALT to bypass replicative senescence.

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Figure 1: STEX analysis of type II survivor formation.
Figure 2: Long telomeres are preferentially extended during type II survivor formation.
Figure 3: Telomerase-negative rifΔ strains show accelerated senescence.
Figure 4: Telomere shortening rate is unchanged when RIF1 and RIF2 are deleted.
Figure 5: Model for the senescence of est2Δ and est2Δ rif1Δ rif2Δ strains.

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References

  1. de Lange, T. How telomeres solve the end-protection problem. Science 326, 948–952 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kim, N.W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Shay, J.W. & Bacchetti, S. A survey of telomerase activity in human cancer. Eur. J. Cancer 33, 787–791 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Greider, C.W. & Blackburn, E.H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985).

    Article  CAS  PubMed  Google Scholar 

  5. Cesare, A.J. & Reddel, R.R. Alternative lengthening of telomeres: models, mechanisms and implications. Nat. Rev. Genet. 11, 319–330 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Le, S., Moore, J.K., Haber, J.E. & Greider, C.W. RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase. Genetics 152, 143–152 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 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  PubMed  PubMed Central  Google Scholar 

  9. Chen, Q., Ijpma, A. & Greider, C.W. Two survivor pathways that allow growth in the absence of telomerase are generated by distinct telomere recombination events. Mol. Cell. Biol. 21, 1819–1827 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lydeard, J.R., Jain, S., Yamaguchi, M. & Haber, J.E. Break-induced replication and telomerase-independent telomere maintenance require Pol32. Nature 448, 820–823 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Teng, S.C., Chang, J., McCowan, B. & Zakian, V.A. Telomerase-independent lengthening of yeast telomeres occurs by an abrupt Rad50p-dependent, Rif-inhibited recombinational process. Mol. Cell 6, 947–952 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Huang, P. et al. SGS1 is required for telomere elongation in the absence of telomerase. Curr. Biol. 11, 125–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Johnson, F.B. et al. The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase. EMBO J. 20, 905–913 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tsukamoto, Y., Taggart, A.K. & Zakian, V.A. The role of the Mre11-Rad50-Xrs2 complex in telomerase- mediated lengthening of Saccharomyces cerevisiae telomeres. Curr. Biol. 11, 1328–1335 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Straatman, K.R. & Louis, E.J. Localization of telomeres and telomere-associated proteins in telomerase-negative Saccharomyces cerevisiae. Chromosome Res. 15, 1033–1050 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bryan, T.M., Englezou, A., Gupta, J., Bacchetti, S. & Reddel, R.R. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J. 14, 4240–4248 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bryan, T.M., Englezou, A., Dalla-Pozza, L., Dunham, M.A. & Reddel, R.R. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat. Med. 3, 1271–1274 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. McEachern, M.J. & Haber, J.E. Break-induced replication and recombinational telomere elongation in yeast. Annu. Rev. Biochem. 75, 111–135 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Henson, J.D. et al. DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity. Nat. Biotechnol. 27, 1181–1185 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Larrivée, M. & Wellinger, R.J. Telomerase- and capping-independent yeast survivors with alternate telomere states. Nat. Cell Biol. 8, 741–747 (2006).

    Article  PubMed  Google Scholar 

  21. Teixeira, M.T., Arneric, M., Sperisen, P. & Lingner, J. Telomere length homeostasis is achieved via a switch between telomerase-extendible and -nonextendible states. Cell 117, 323–335 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Arnerić, M. & Lingner, J. Tel1 kinase and subtelomere-bound Tbf1 mediate preferential elongation of short telomeres by telomerase in yeast. EMBO Rep. 8, 1080–1085 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lingner, J. et al. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561–567 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Förstemann, K., Hoss, M. & Lingner, J. Telomerase-dependent repeat divergence at the 3′ ends of yeast telomeres. Nucleic Acids Res. 28, 2690–2694 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee, J.Y., Kozak, M., Martin, J.D., Pennock, E. & Johnson, F.B. Evidence that a RecQ helicase slows senescence by resolving recombining telomeres. PLoS Biol. 5, e160 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kozak, M.L. et al. Inactivation of the Sas2 histone acetyltransferase delays senescence driven by telomere dysfunction. EMBO J. 29, 158–170 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Hardy, C.F., Sussel, L. & Shore, D.A. RAP1-interacting protein involved in transcriptional silencing and telomere length regulation. Genes Dev. 6, 801–814 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Wotton, D. & Shore, D. A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Genes Dev. 11, 748–760 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Bonetti, D. et al. Shelterin-like proteins and Yku inhibit nucleolytic processing of Saccharomyces cerevisiae telomeres. PLoS Genet. 6, e1000966 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hemann, M.T., Strong, M.A., Hao, L.Y. & Greider, C.W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Khadaroo, B. et al. The DNA damage response at eroded telomeres and tethering to the nuclear pore complex. Nat. Cell Biol. 11, 980–987 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Abdallah, P. et al. A two-step model for senescence triggered by a single critically short telomere. Nat. Cell Biol. 11, 988–993 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Britt-Compton, B., Capper, R., Rowson, J. & Baird, D.M. Short telomeres are preferentially elongated by telomerase in human cells. FEBS Lett. 583, 3076–3080 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Singer, B.S., Gold, L., Gauss, P. & Doherty, D.H. Determination of the amount of homology required for recombination in bacteriophage T4. Cell 31, 25–33 (1982).

    Article  CAS  PubMed  Google Scholar 

  36. Watt, V.M., Ingles, C.J., Urdea, M.S. & Rutter, W.J. Homology requirements for recombination in Escherichia coli. Proc. Natl. Acad. Sci. USA 82, 4768–4772 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shen, P. & Huang, H.V. Homologous recombination in Escherichia coli: dependence on substrate length and homology. Genetics 112, 441–457 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Jinks-Robertson, S., Michelitch, M. & Ramcharan, S. Substrate length requirements for efficient mitotic recombination in Saccharomyces cerevisiae. Mol. Cell. Biol. 13, 3937–3950 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rubnitz, J. & Subramani, S. The minimum amount of homology required for homologous recombination in mammalian cells. Mol. Cell. Biol. 4, 2253–2258 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liskay, R.M., Letsou, A. & Stachelek, J.L. Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells. Genetics 115, 161–167 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Pâques, F. & Haber, J.E. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 63, 349–404 (1999).

    PubMed  PubMed Central  Google Scholar 

  42. Grandin, N. & Charbonneau, M. Telomerase- and Rad52-independent immortalization of budding yeast by an inherited-long-telomere pathway of telomeric repeat amplification. Mol. Cell. Biol. 29, 965–985 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Lebel, C. et al. Telomere maintenance and survival in Saccharomyces cerevisiae in the absence of telomerase and RAD52. Genetics 182, 671–684 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Levy, D.L. & Blackburn, E.H. Counting of Rif1p and Rif2p on Saccharomyces cerevisiae telomeres regulates telomere length. Mol. Cell. Biol. 24, 10857–10867 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sherman, F. Getting started with yeast. Methods Enzymol. 194, 3–21 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Janeja, V.P. & Atluri, V. LS3: a linear semantic scan statistic technique for detecting anomalous windows. ACM Symp. Applied Computing 493–497 (2005).

  47. Shi, L. & Janeja, V.P. Anomalous window discovery through scan statistics for linear intersecting paths (SSLIP). Proc. 15th ACM SIGKDD Int. Conf. Knowledge Discovery and Data Mining 767–775 (2009).

  48. Dionne, I. & Wellinger, R.J. Cell cycle-regulated generation of single-stranded G-rich DNA in the absence of telomerase. Proc. Natl. Acad. Sci. USA 93, 13902–13907 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank K. Bernstein, B. Luke and P. Thorpe for comments on the manuscript. M.C. was supported by a Long-term Fellowship Award from the International Human Frontier Science Program (HFSP) organization and a Terry Fox Foundation Fellowship Award. This work was supported by funds from the US National Institutes of Health (CA009503 and GM008798 to J.C.D.; GM50237 to R.R.).

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Authors and Affiliations

  1. Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA

    Michael Chang & Rodney Rothstein

  2. Department of Biological Sciences, Columbia University, New York, New York, USA

    John C Dittmar

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M.C. designed and carried out the experiments, analyzed the data and wrote the manuscript. J.C.D. did the statistical analysis of the STEX data. R.R. helped to analyze the data and write the manuscript.

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Correspondence to Michael Chang.

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Chang, M., Dittmar, J. & Rothstein, R. Long telomeres are preferentially extended during recombination-mediated telomere maintenance. Nat Struct Mol Biol 18, 451–456 (2011). https://doi.org/10.1038/nsmb.2034

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