Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A DNA-hairpin model for repeat-addition processivity in telomere synthesis

Nature Structural & Molecular Biology volume 22, pages 844–847 (2015)Cite this article

Subjects

Abstract

We propose a DNA-hairpin model for the processivity of telomeric-repeat addition. Concomitantly with template-RNA translocation after each repeat synthesis, the complementary DNA repeat, for example, AGGGTT, loops out in a noncanonical base-paired hairpin, thus freeing the RNA template for the next round of repeat synthesis. The DNA hairpin is temporarily stabilized by telomerase and the incoming dGTP but becomes realigned for processive telomere synthesis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Telomerase.
Figure 2: Telomeric repeats.
Figure 3: The structural cavity and flexibility of TERT accommodate the DNA-hairpin loopout.
Figure 4: A DNA-hairpin model for repeat-addition processivity.

Accession codes

Accessions

Protein Data Bank

References

  1. Blackburn, E.H. Nature 350, 569–573 (1991).

    Article  CAS  Google Scholar 

  2. Berman, A.J. & Cech, T.R. Cell 151, 1138–1138.e1 (2012).

    Article  CAS  Google Scholar 

  3. Greider, C.W. Curr. Biol. 8, R178–R181 (1998).

    Article  CAS  Google Scholar 

  4. Autexier, C. & Greider, C.W. Genes Dev. 8, 563–575 (1994).

    Article  CAS  Google Scholar 

  5. Nakamura, T.M. et al. Science 277, 955–959 (1997).

    Article  CAS  Google Scholar 

  6. Gillis, A.J., Schuller, A.P. & Skordalakes, E. Nature 455, 633–637 (2008).

    Article  CAS  Google Scholar 

  7. Mitchell, M., Gillis, A., Futahashi, M., Fujiwara, H. & Skordalakes, E. Nat. Struct. Mol. Biol. 17, 513–518 (2010).

    Article  CAS  Google Scholar 

  8. Harkisheimer, M., Mason, M., Shuvaeva, E. & Skordalakes, E. Structure 21, 1870–1878 (2013).

    Article  CAS  Google Scholar 

  9. Huang, J. et al. Nat. Struct. Mol. Biol. 21, 507–512 (2014).

    Article  CAS  Google Scholar 

  10. Wu, R.A. & Collins, K. Proc. Natl. Acad. Sci. USA 111, 11234–11235 (2014).

    Article  CAS  Google Scholar 

  11. Robart, A.R. & Collins, K. Mol. Cell 42, 308–318 (2011).

    Article  CAS  Google Scholar 

  12. Greider, C.W. & Blackburn, E.H. Nature 337, 331–337 (1989).

    Article  CAS  Google Scholar 

  13. Berman, A.J., Akiyama, B.M., Stone, M.D. & Cech, T.R. Nat. Struct. Mol. Biol. 18, 1371–1375 (2011).

    Article  CAS  Google Scholar 

  14. Wu, R.A. & Collins, K. EMBO J. 33, 921–935 (2014).

    Article  CAS  Google Scholar 

  15. Parks, J.W. & Stone, M.D. Nat. Commun. 5, 4146 (2014).

    Article  CAS  Google Scholar 

  16. Brown, A.F. et al. Proc. Natl. Acad. Sci. USA 111, 11311–11316 (2014).

    Article  CAS  Google Scholar 

  17. Podlevsky, J.D., Bley, C.J., Omana, R.V., Qi, X. & Chen, J.J. Nucleic Acids Res. 36, D339–D343 (2008).

    Article  CAS  Google Scholar 

  18. Chen, J.L., Blasco, M.A. & Greider, C.W. Cell 100, 503–514 (2000).

    Article  CAS  Google Scholar 

  19. Adams, S.P. et al. Proc. Biol. Sci. 268, 1541–1546 (2001).

    Article  CAS  Google Scholar 

  20. Williamson, J.R., Raghuraman, M.K. & Cech, T.R. Cell 59, 871–880 (1989).

    Article  CAS  Google Scholar 

  21. Schaffitzel, C. et al. Proc. Natl. Acad. Sci. USA 98, 8572–8577 (2001).

    Article  CAS  Google Scholar 

  22. Biffi, G., Tannahill, D., McCafferty, J. & Balasubramanian, S. Nat. Chem. 5, 182–186 (2013).

    Article  CAS  Google Scholar 

  23. Sfeir, A. et al. Cell 138, 90–103 (2009).

    Article  CAS  Google Scholar 

  24. Lormand, J.D. et al. Nucleic Acids Res. 41, 10323–10333 (2013).

    Article  CAS  Google Scholar 

  25. Jarstfer, M.B. & Cech, T.R. Biochemistry 41, 151–161 (2002).

    Article  CAS  Google Scholar 

  26. Barabas, O. et al. Cell 132, 208–220 (2008).

    Article  CAS  Google Scholar 

  27. Padrta, P., Stefl, R., Kralik, L., Zidek, L. & Sklenar, V. J. Biomol. NMR 24, 1–14 (2002).

    Article  CAS  Google Scholar 

  28. Yang, W. & Woodgate, R. Proc. Natl. Acad. Sci. USA 104, 15591–15598 (2007).

    Article  CAS  Google Scholar 

  29. Huang, H., Chopra, R., Verdine, G.L. & Harrison, S.C. Science 282, 1669–1675 (1998).

    Article  CAS  Google Scholar 

  30. Lee, Y.S., Gao, Y. & Yang, W. Nat. Struct. Mol. Biol. 22, 298–303 (2015).

    Article  CAS  Google Scholar 

  31. Kohlstaedt, L.A., Wang, J., Friedman, J.M., Rice, P.A. & Steitz, T.A. Science 256, 1783–1790 (1992).

    Article  CAS  Google Scholar 

  32. Sauerwald, A. et al. Nat. Struct. Mol. Biol. 20, 454–460 (2013).

    Article  CAS  Google Scholar 

  33. Hardy, C.D., Schultz, C.S. & Collins, K. J. Biol. Chem. 276, 4863–4871 (2001).

    Article  CAS  Google Scholar 

  34. Drosopoulos, W.C. & Prasad, V.R. Nucleic Acids Res. 35, 1155–1168 (2007).

    Article  CAS  Google Scholar 

  35. Drosopoulos, W.C. & Prasad, V.R. Mol. Cell. Biol. 30, 447–459 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Collins for guiding us throughout the project, J.-L. Chen and T.R. Cech for insightful discussion, J.P. Cooper, T. de Lange, C.W. Greider, D. Rhodes and M.D. Stone for encouragement and D.J. Leahy and M. Gellert for critical reading of the manuscript. This work was funded by the US National Institutes of Health Intramural Program (DK036146-08 to W.Y.).

Author information

Authors and Affiliations

  1. Wei Yang is at the Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.,

    Wei Yang

  2. Young-Sam Lee is at the Well-Aging Research Center, Samsung Advanced Institute of Technology, Suwon, Korea.,

    Young-Sam Lee

Authors
  1. Wei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young-Sam Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Yang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Structural differences between p66 and p51 subunits of HIV-1 RT and unfolding of the β-linker.

After superposition of the palm domains in p51 and p66 (PDB 1RTD)29, the movement of the thumb (green) in the two subunits is morphed. The β-linker (pink) between the thumb and palm domain (made of three β-strands) is unfolded in the p51 subunit. (MOV 757 kb)

Animation of the DNA hairpin model.

At the end of each cycle of repeat addition, while the RNA template (dark red) and DNA primer (orange) hybrid is translocated together, the 3′ end of DNA remains in the active site of TERT (shown as an outlined pink oval), and one telomeric repeat, e.g. AGGGTT, is looped out. The underscored T, which is recognized by TRBD as a signal for pausing DNA hairpin formation, is highlighted in olive color. Binding of the incoming dGTP stabilizes the hairpin loopout and also promotes the DNA realignment for the next round of repeat synthesis. (MOV 1349 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, W., Lee, YS. A DNA-hairpin model for repeat-addition processivity in telomere synthesis. Nat Struct Mol Biol 22, 844–847 (2015). https://doi.org/10.1038/nsmb.3098

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.3098

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing