Structural and Functional Analysis of the Human POT1-TPP1 Telomeric Complex

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Apr 11

PMID 28393830

Citations 60

Authors

Cory Rice

Prashanth Krishna Shastrula

Andrew V Kossenkov

Robert Hills

Duncan M Baird

Louise C Showe

Tzanko Doukov

Susan Janicki

Emmanuel Skordalakes

Affiliations

Soon will be listed here.

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.

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