An Improved Model for the hTERT Promoter Quadruplex

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.

[1]  J. Bishop,et al.  BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  David M. Jameson,et al.  Introduction to Fluorescence , 2014 .

[3]  M. Komiyama,et al.  Evidence for G‐Quadruplex DNA in Human Cells , 2013, Chembiochem : a European journal of chemical biology.

[4]  Shankar Balasubramanian,et al.  G-Quadruplex structures are stable and detectable in human genomic DNA , 2013, Nature Communications.

[5]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[6]  Gary L. Gallia,et al.  TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal , 2013, Proceedings of the National Academy of Sciences.

[7]  D. Schadendorf,et al.  TERT Promoter Mutations in Familial and Sporadic Melanoma , 2013, Science.

[8]  Levi C. T. Pierce,et al.  Routine Access to Millisecond Time Scale Events with Accelerated Molecular Dynamics , 2012, Journal of chemical theory and computation.

[9]  E. Novellino,et al.  Topological characterization of nucleic acid G-quadruplexes by UV absorption and circular dichroism. , 2011, Angewandte Chemie.

[10]  J. García de la Torre,et al.  Prediction of hydrodynamic and other solution properties of rigid proteins from atomic- and residue-level models. , 2011, Biophysical journal.

[11]  S. Cacchione,et al.  Self-organization of G-quadruplex structures in the hTERT core promoter stabilized by polyaminic side chain perylene derivatives. , 2010, Biophysical chemistry.

[12]  Kah Wai Lim,et al.  Coexistence of two distinct G-quadruplex conformations in the hTERT promoter. , 2010, Journal of the American Chemical Society.

[13]  A. Lane,et al.  Resolution and characterization of the structural polymorphism of a single quadruplex-forming sequence , 2010, Nucleic acids research.

[14]  D. Corey.  Telomeres and telomerase: from discovery to clinical trials. , 2009, Chemistry & biology.

[15]  L. Hurley,et al.  Formation of a unique end-to-end stacked pair of G-quadruplexes in the hTERT core promoter with implications for inhibition of telomerase by G-quadruplex-interactive ligands. , 2009, Journal of the American Chemical Society.

[16]  J. Chaires,et al.  The tail of the telomere. , 2008, Journal of the American Chemical Society.

[17]  R. Memmott,et al.  A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity , 2008, Nucleic acids research.

[18]  J. Shay,et al.  Targeting telomerase for cancer therapeutics , 2008, British Journal of Cancer.

[19]  D. Pang,et al.  G-quadruplex formation in human telomeric (TTAGGG)4 sequence with complementary strand in close vicinity under molecularly crowded condition , 2007, Nucleic acids research.

[20]  E. Hiyama,et al.  Telomere and telomerase in stem cells , 2007, British Journal of Cancer.

[21]  Sarah W. Burge,et al.  Quadruplex DNA: sequence, topology and structure , 2006, Nucleic acids research.

[22]  Roger A. Jones,et al.  NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region , 2006, Nucleic acids research.

[23]  S. Cogoi,et al.  G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription , 2006, Nucleic acids research.

[24]  Roger A. Jones,et al.  An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution. , 2006, Journal of the American Chemical Society.

[25]  Daekyu Sun,et al.  Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1alpha promoter. , 2005, Biochemistry.

[26]  S. Neidle,et al.  Highly prevalent putative quadruplex sequence motifs in human DNA , 2005, Nucleic acids research.

[27]  Shankar Balasubramanian,et al.  Prevalence of quadruplexes in the human genome , 2005, Nucleic acids research.

[28]  Roger A. Jones,et al.  Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Implications for G-quadruplex stabilization. , 2005, Biochemistry.

[29]  G. Parkinson,et al.  The structure of telomeric DNA. , 2003, Current opinion in structural biology.

[30]  D. Bearss,et al.  Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Schuck,et al.  Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling. , 2000, Biophysical journal.

[32]  M. Kubista,et al.  The interactions between the fluorescent dye thiazole orange and DNA. , 1998, Biopolymers.

[33]  J. Shay,et al.  A survey of telomerase activity in human cancer. , 1997, European journal of cancer.

[34]  Alastair I.H. Murchie,et al.  Retinoblastoma susceptibility genes contain 5' sequences with a high propensity to form guanine-tetrad structures , 1992, Nucleic Acids Res..

[35]  Aaron Klug,et al.  Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops , 1989, Nature.

[36]  D. Davies,et al.  Helix formation by guanylic acid. , 1962, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Shankar Balasubramanian,et al.  Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells. , 2014, Nature chemistry.

[38]  J. Chaires,et al.  Calculation of hydrodynamic properties for G-quadruplex nucleic acid structures from in silico bead models. , 2013, Topics in current chemistry.

[39]  E. Hiyama,et al.  Telomere and Telomerase for the Regulation of Stem Cells , 2009 .

[40]  L. Montanaro,et al.  Fluorescence polarization of elongation factor 2. , 1979, Methods in enzymology.

[41]  L. Montanaro,et al.  [64] Fluorescence polarization of elongation factor 2 , 1979 .

[42]  D. Schadendorf,et al.  Highly Recurrent TERT Promoter Mutations in Human Melanoma , 2022 .