Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

The Unprecedented Structure of a G-quadruplex Formed in the Human c-kit Promoter

The c-kit oncogene encodes 145-160 kDa receptor tyrosine kinase. Over-expression of this oncogene or mutations alter the cellular signal transduction flow in a way that impairs normal cell functioning. Malignant transformations such as human gastrointestinal stromal tumor, myeloid leukemias and human germ line tumors are known to be associated with the activity of the c-kit gene. The part of its promoter region including a transcription activation site, contains G-rich sequences. Recent biophysical data including NMR, have shown that two fragments of this region can form G-quadruplex structures.

Here, we present the structure of a quadruplex from the c-kit promoter region. Molecular details and schematics of the structure are shown in the Figure. The structure, being a member of parallel-stranded G-quadruplexes with all-anti guanines, has unique and unprecedented features. Most strikingly, an isolated guanine from the CGCT fragment of the sequence (underlined) is involved in G tetrad core formation. Insertion of the isolated G forms a characteristic broken strand topology in the quadruplex core (indicated by an arrow). There are four loops: two single-residue double-chain-reversal loops, a two-residue loop and a five-residue stem-loop, which contain base-pairing alignments.

The structure is formed by folding of a single strand and thus its formation in the promoter region might result as a response to interaction with ligands and/or proteins. The structure represents a potential target in promoter regulation and drug design.

References and Footnotes
  1. A. T. Phan, V. Kuryavyi, S. Burge, S. Neidle, D. J. Patel. Journal of American Chemical Society in press (2007).

Anh Tuân Phan1, 3
Vitaly Kuryavyi1, *
Sarah Burge2, 4
Stephen Neidle2
Dinshaw J. Patel1

1Structural Biology Program
Memorial Sloan-Kettering Cancer Center
New York, NY 10021, USA
2Cancer Research UK Biomolecular Structure Group
School of Pharmacy
University of London
London WC1N 1AX, UK
3Present address:
Division of Physics and Applied Physics
School of Physical and Mathematical Sciences
Nanyang Technological University
4Present address:
MRC Centre for Protein Engineering
Cambridge, CB2 2QH, UK

*Email: kuryavyv@mskcc.org