Telomere protection by mammalian Pot1 requires interaction with Tpp1 (original) (raw)

Nature Structural & Molecular Biology volume 14, pages 754–761 (2007)Cite this article

A Corrigendum to this article was published on 01 May 2009

This article has been updated

Abstract

The shelterin complex at mammalian telomeres contains the single-stranded DNA–binding protein Pot1, which regulates telomere length and protects chromosome ends. Pot1 binds Tpp1, the shelterin component that connects Pot1 to the duplex telomeric DNA–binding proteins Trf1 and Trf2. Control of telomere length requires that Pot1 binds Tpp1 as well as the single-stranded telomeric DNA, but it is not known whether the protective function of Pot1 depends on Tpp1. Alternatively, Pot1 might function similarly to the Pot1-like proteins of budding and fission yeast, which have no known Tpp1-like connection to the duplex telomeric DNA. Using mutant mouse cells with diminished Tpp1 levels, RNA interference directed to mouse Tpp1 and Pot1, and complementation of mouse Pot1 knockout cells with human and mouse Pot1 variants, we show here that Tpp1 is required for the protective function of mammalian Pot1 proteins.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

USD 39.95

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

Additional access options:

Similar content being viewed by others

Change history

In the version of this article initially published, one of the US National Institutes of Health grant numbers was incorrect. The correct acknowledgment should be: "US National Institutes of Health to T.d.L. (GM49046 and AG016642)." The error has been corrected in the HTML and PDF versions of the article.

References

  1. de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005).
    Article CAS Google Scholar
  2. Baumann, P. & Cech, T.R. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292, 1171–1175 (2001).
    Article CAS Google Scholar
  3. Veldman, T., Etheridge, K.T. & Counter, C.M. Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Curr. Biol. 14, 2264–2270 (2004).
    Article CAS Google Scholar
  4. Yang, Q., Zheng, Y.L. & Harris, C.C. POT1 and TRF2 cooperate to maintain telomeric integrity. Mol. Cell. Biol. 25, 1070–1080 (2005).
    Article CAS Google Scholar
  5. Hockemeyer, D., Sfeir, A.J., Shay, J.W., Wright, W.E. & de Lange, T. POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J. 24, 2667–2678 (2005).
    Article CAS Google Scholar
  6. Hockemeyer, D., Daniels, J.P., Takai, H. & de Lange, T. Recent expansion of the telomeric complex in rodents: two distinct POT1 proteins protect mouse telomeres. Cell 126, 63–77 (2006).
    Article CAS Google Scholar
  7. Wu, L. et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 126, 49–62 (2006).
    Article CAS Google Scholar
  8. He, H. et al. POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination. EMBO J. 25, 5180–5190 (2006).
    Article CAS Google Scholar
  9. Wang, F. et al. The POT1–TPP1 telomere complex is a telomerase processivity factor. Nature 445, 506–510 (2007).
    Article CAS Google Scholar
  10. Kim, S.H., Kaminker, P. & Campisi, J. TIN2, a new regulator of telomere length in human cells. Nat. Genet. 23, 405–412 (1999).
    Article CAS Google Scholar
  11. Ye, J.Z. et al. TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J. Biol. Chem. 279, 47264–47271 (2004).
    Article CAS Google Scholar
  12. Ye, J.Z. et al. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 18, 1649–1654 (2004).
    Article CAS Google Scholar
  13. Liu, D. et al. PTOP interacts with POT1 and regulates its localization to telomeres. Nat. Cell Biol. 6, 673–680 (2004).
    Article CAS Google Scholar
  14. Kim, S.H. et al. TIN2 mediates functions of TRF2 at human telomeres. J. Biol. Chem. 279, 43799–43804 (2004).
    Article CAS Google Scholar
  15. Houghtaling, B.R., Cuttonaro, L., Chang, W. & Smith, S. A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr. Biol. 14, 1621–1631 (2004).
    Article CAS Google Scholar
  16. Loayza, D. & de Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013–1018 (2003).
    Article CAS Google Scholar
  17. Smogorzewska, A. & de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004).
    Article CAS Google Scholar
  18. Keegan, C.E. et al. Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. Hum. Mol. Genet. 14, 113–123 (2005).
    Article CAS Google Scholar
  19. O'Connor, M.S., Safari, A., Xin, H., Liu, D. & Songyang, Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc. Natl. Acad. Sci. USA 103, 11874–11879 (2006).
    Article CAS Google Scholar
  20. van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998).
    Article CAS Google Scholar
  21. Celli, G.B. & de Lange, T. DNA processing not required for ATM-mediated telomere damage response after TRF2 deletion. Nat. Cell Biol. 7, 712–718 (2005).
    Article CAS Google Scholar
  22. Celli, G.B., Lazzerini Denchi, E. & de Lange, T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat. Cell Biol. 8, 885–890 (2006).
    Article Google Scholar
  23. Xin, H. et al. TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 445, 559–562 (2007).
    Article CAS Google Scholar
  24. Griffith, J.D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999).
    Article CAS Google Scholar

Download references

Acknowledgements

We thank M. Lei for communicating his findings on the structure of TPP1 before publication, and E. Lazzerini Denchi, K. Hoke and A. Sfeir for insightful comments on this manuscript. J.-P.D. and W.P. were supported by the Studienstiftung des deutschen Volkes. D.H. was supported by a Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology Grant and Rockefeller University Graduate Program Funds. T.E. was supported by the Deutche Forschungsgemeinschaft (DFG EL265/I). This work was supported by grants from the US National Institutes of Health to T.d.L. (GM49046 and AG016642), G.D.H. (DK62027 and DK65313) and C.E.K. (K08-HD42487) and by a March of Dimes Basil O'Connor Award to C.E.K.

Author information

Author notes

  1. Jan-Peter Daniels & Jeffrey Z-S Ye
    Present address: Current addresses: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK (J.-P.D.) and Department of Oncology, Kaiser Permanente Medical Group, Santa Rosa, California 95403, USA (J.Z.-S.Y.).,

Authors and Affiliations

  1. Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, 10065, New York, USA
    Dirk Hockemeyer, Wilhelm Palm, Jan-Peter Daniels, Kaori K Takai & Titia de Lange
  2. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Health System, 109 Zina Pitcher Pl., Ann Arbor, 48109-0789, Michigan, USA
    Tobias Else & Gary D Hammer
  3. Division of Hematology, New York University School of Medicine, 650 First Avenue, New York, 10016, New York, USA
    Jeffrey Z-S Ye
  4. Department of Pediatrics, Division of Genetics, University of Michigan, 1150 W. Medical Center Dr., Ann Arbor, 48109-0652, Michigan, USA
    Catherine E Keegan

Authors

  1. Dirk Hockemeyer
  2. Wilhelm Palm
  3. Tobias Else
  4. Jan-Peter Daniels
  5. Kaori K Takai
  6. Jeffrey Z-S Ye
  7. Catherine E Keegan
  8. Titia de Lange
  9. Gary D Hammer

Contributions

D.H. designed and performed the experiments, with W.P. contributing in the later stages of the project. J.-P.D. and K.K.T. contributed to the experiments in the supplementary figures. G.D.H., C.E.K. and T.E. generated the _Tpp1_acd/acd cells used in this study. J.Z.-S.Y. generated the TPP1 antibodies. T.d.L. wrote the paper and made the figures.

Corresponding author

Correspondence toTitia de Lange.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Hockemeyer, D., Palm, W., Else, T. et al. Telomere protection by mammalian Pot1 requires interaction with Tpp1.Nat Struct Mol Biol 14, 754–761 (2007). https://doi.org/10.1038/nsmb1270

Download citation

This article is cited by