An improved model for the hTERT promoter quadruplex.

Jonathan B Chaires,John O Trent,Donald M Miller,Shelia D Thomas,Robert Buscaglia,Robert D Gray,William L Dean,Mark Isalan

doi:10.1371/journal.pone.0115580

Abstract

Mutations occur at four specific sites in the hTERT promoter in >75% of glioblastomas and melanomas, but the mechanism by which the mutations affect gene expression remains unexplained. We report biophysical computational studies that show that the hTERT promoter sequence forms a novel G-quadruplex structure consisting of three contiguous, stacked parallel quadruplexes. The reported hTERT mutations map to the central quadruplex within this structure, and lead to an alteration of its hydrodynamic properties and stability.

Highlights

Over the past decade, genomic DNA sequencing efforts have revealed the broad mutational landscapes of common human cancers [1]
Using whole genome sequencing data, several groups have recently shown that mutations occur at four specific sites in the hTERT promoter [2,3,4] in .75% of glioblastomas and melanomas
We noticed that these mutations all occur in a G-rich region of the hTERT promoter which has previously been shown to form quadruplex DNA [6]

Summary

Introduction

Genomic DNA sequencing efforts have revealed the broad mutational landscapes of common human cancers [1]. The guanine to adenine mutations create a new binding site for the E-twenty six (ETS) transcription factor, which has been hypothesized to be the mechanism of increased hTERT expression [2, 3]. We noticed that these mutations all occur in a G-rich region of the hTERT promoter which has previously been shown to form quadruplex DNA [6]. These sequences can form either intramolecular or intermolecular Hoogsteen hydrogen bonds stabilizing their secondary and tertiary structure [8, 11]. The mutations may alter the stability and molecular recognition of the hTERT quadruplex

Materials and Methods

Results and Discussion

Methods