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

Cory Rice, Prashanth Krishna Shastrula, Andrew V. Kossenkov, Robert Hills, Duncan M. Baird, Louise C. Showe, Tzanko Doukov, Susan Janicki and Emmanuel Skordalakes ()
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Cory Rice: The Wistar Institute
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

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14928

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