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

Rice, Cory, Shastrula, Prashanth Krishna, Kossenkov, Andrew V., Hills, Robert Kerrin ORCID: https://orcid.org/0000-0003-0166-0062, Baird, Duncan Martin ORCID: https://orcid.org/0000-0001-8408-5467, Showe, Louise C., Doukov, Tzanko, Janicki, Susan and Skordalakes, Emmanuel 2017. Structural and functional analysis of the human POT1-TPP1 telomeric complex. Nature Communications 8 , 14928. 10.1038/ncomms14928

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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 cancerassociated 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
Date of First Compliant Deposit:	24 April 2017
Date of Acceptance:	14 February 2017
Last Modified:	07 May 2023 09:50
URI:	https://orca.cardiff.ac.uk/id/eprint/100034

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