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

Rice, Cory; Shastrula, Prashanth Krishna; Kossenkov, Andrew V.; Hills, Robert; Baird, Duncan M.; Showe, Louise C.; Doukov, Tzanko; Janicki, Susan; Skordalakes, Emmanuel

doi:10.1038/ncomms14928

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

Journal Article · Mon Apr 10 00:00:00 EDT 2017 · Nature Communications

DOI:https://doi.org/10.1038/ncomms14928· OSTI ID:1361138

Rice, Cory ^[1]; Shastrula, Prashanth Krishna ^[2]; Kossenkov, Andrew V. ^[2]; Hills, Robert ^[2]; Baird, Duncan M. ^[3]; Showe, Louise C. ^[2]; Doukov, Tzanko ^[4]; Janicki, Susan ^[2]; Skordalakes, Emmanuel ^[1]

The Wistar Inst., Philadelphia, PA (United States); Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine. Dept. of Biochemistry and Biophysics
The Wistar Inst., Philadelphia, PA (United States)
Cardiff Univ. (United Kingdom). School of Medicine. Division of Cancer and Genetics
SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States); The Wistar Inst., Philadelphia, PA (United States)

Sponsoring Organization:: National Inst. of Health (NIH) (United States); USDOE; Wistar Cancer Center (United States)

Contributing Organization:: Cardiff Univ. (United Kingdom); Univ. of Pennsylvania, Philadelphia, PA (United States)

Grant/Contract Number:: AC02-05CH11231; AC02-76SF00515

OSTI ID:: 1361138

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 8; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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