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Structural and functional analysis of the human POT1-TPP1 telomeric complex

Author

Listed:
  • Cory Rice

    (The Wistar Institute
    Perelman School of Medicine, University of Pennsylvania)

  • Prashanth Krishna Shastrula

    (The Wistar Institute)

  • Andrew V. Kossenkov

    (The Wistar Institute)

  • Robert Hills

    (The Wistar Institute)

  • Duncan M. Baird

    (School of Medicine, Cardiff University)

  • Louise C. Showe

    (The Wistar Institute)

  • Tzanko Doukov

    (Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University)

  • Susan Janicki

    (The Wistar Institute)

  • Emmanuel Skordalakes

    (The Wistar Institute
    Perelman School of Medicine, University of Pennsylvania)

Abstract

POT1 and TPP1 are part of the shelterin complex and are essential for telomere length regulation and maintenance. Naturally occurring mutations of the telomeric POT1–TPP1 complex are implicated in familial glioma, melanoma and chronic lymphocytic leukaemia. Here we report the atomic structure of the interacting portion of the human telomeric POT1–TPP1 complex and suggest how several of these mutations contribute to malignant cancer. The POT1 C-terminus (POT1C) forms a bilobal structure consisting of an OB-fold and a holiday junction resolvase domain. TPP1 consists of several loops and helices involved in extensive interactions with POT1C. Biochemical data shows that several of the cancer-associated mutations, partially disrupt the POT1–TPP1 complex, which affects its ability to bind telomeric DNA efficiently. A defective POT1–TPP1 complex leads to longer and fragile telomeres, which in turn promotes genomic instability and cancer.

Suggested Citation

  • Cory Rice & Prashanth Krishna Shastrula & Andrew V. Kossenkov & Robert Hills & Duncan M. Baird & Louise C. Showe & Tzanko Doukov & Susan Janicki & Emmanuel Skordalakes, 2017. "Structural and functional analysis of the human POT1-TPP1 telomeric complex," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14928
    DOI: 10.1038/ncomms14928
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