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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.

Original publication

DOI

10.1038/ncomms14928

Type

Journal article

Journal

Nat Commun

Publication Date

10/04/2017

Volume

8

Keywords

Calorimetry, Crystallography, X-Ray, DNA, HEK293 Cells, Humans, Mutant Proteins, Mutation, Protein Binding, Structure-Activity Relationship, Telomerase, Telomere, Telomere-Binding Proteins