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

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.

Authors:
 [1];  [2];  [2];  [2];  [3];  [2];  [4];  [2];  [1]
  1. The Wistar Inst., Philadelphia, PA (United States); Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine. Dept. of Biochemistry and Biophysics
  2. The Wistar Inst., Philadelphia, PA (United States)
  3. Cardiff Univ. (United Kingdom). School of Medicine. Division of Cancer and Genetics
  4. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource
Publication Date:
Research Org.:
The Wistar Inst., Philadelphia, PA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States); Wistar Cancer Center (United States)
Contributing Org.:
Cardiff Univ. (United Kingdom); Univ. of Pennsylvania, Philadelphia, PA (United States)
OSTI Identifier:
1361138
Grant/Contract Number:  
AC02-76SF00515; AC02-05CH11231; P41GM103393; R01 GM088332; R01 CA201312; P30 CA10815
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE; X-ray crystallography; Telomeres; Mechanisms of disease

Citation Formats

Rice, Cory, Shastrula, Prashanth Krishna, Kossenkov, Andrew V., Hills, Robert, Baird, Duncan M., Showe, Louise C., Doukov, Tzanko, Janicki, Susan, and Skordalakes, Emmanuel. Structural and functional analysis of the human POT1-TPP1 telomeric complex. United States: N. p., 2017. Web. doi:10.1038/ncomms14928.
Rice, Cory, Shastrula, Prashanth Krishna, Kossenkov, Andrew V., Hills, Robert, Baird, Duncan M., Showe, Louise C., Doukov, Tzanko, Janicki, Susan, & Skordalakes, Emmanuel. Structural and functional analysis of the human POT1-TPP1 telomeric complex. United States. doi:10.1038/ncomms14928.
Rice, Cory, Shastrula, Prashanth Krishna, Kossenkov, Andrew V., Hills, Robert, Baird, Duncan M., Showe, Louise C., Doukov, Tzanko, Janicki, Susan, and Skordalakes, Emmanuel. Mon . "Structural and functional analysis of the human POT1-TPP1 telomeric complex". United States. doi:10.1038/ncomms14928. https://www.osti.gov/servlets/purl/1361138.
@article{osti_1361138,
title = {Structural and functional analysis of the human POT1-TPP1 telomeric complex},
author = {Rice, Cory and Shastrula, Prashanth Krishna and Kossenkov, Andrew V. and Hills, Robert and Baird, Duncan M. and Showe, Louise C. and Doukov, Tzanko and Janicki, Susan and Skordalakes, Emmanuel},
abstractNote = {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.},
doi = {10.1038/ncomms14928},
journal = {Nature Communications},
number = ,
volume = 8,
place = {United States},
year = {2017},
month = {4}
}

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