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Telomere protection by mammalian Pot1 requires interaction with Tpp1

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

A Corrigendum to this article was published on 01 May 2009

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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.

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Figure 1: Dependence of Pot1a and Pot1b telomeric localization on Tpp1.
Figure 2: Human POT1 can be targeted to mouse telomeres by human TPP1.
Figure 3: Telomere deprotection associated with reduced Tpp1 abundance.
Figure 4: Dominant-negative interference between Pot1a and Pot1b.
Figure 5: Human POT1 complements Pot1a loss when coexpressed with human TPP1.
Figure 6: Trf2 affects the telomeric accumulation of Pot1a and Pot1b.

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  • 24 November 2008

    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.

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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.

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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

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  1. Dirk Hockemeyer
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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 Tpp1acd/acd cells used in this study. J.Z.-S.Y. generated the TPP1 antibodies. T.d.L. wrote the paper and made the figures.

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Correspondence to Titia de Lange.

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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

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