Insights of potential G-quadruplex sequences in telomeres and proto-oncogenes

Abstract

www.onk.ns.ac.rs/Archive Vol 21, No. 3-4, December 2013 INTRODUCTION The earliest research in the antineoplastic drug discovery was related to suppressing the synthesis and function of DNA. Today, a variety of other targets is under intensive investigation and they will provide oncologist with significant new approaches of therapy. Some of these approaches are inhibition of protease involved in metastasis, angiogenesis inhibitors, antisense technology, and G-quadruplexes. G-quadruplexes are generally formed in DNA and RNA sequences containing repeated G-G-G-G called as G-tetrad. G-quadruplexes formed from planar stacking of hoogsteen bonded G-tetrads (1, 2) folded from a single G-rich sequence by intraor inter-molecular association of 2 to 4 separate strands (3, 4). The core of G-quadruplexes are formed by the stacking of several G-tetrads and joined together by sugar phosphate backbone. The binding energy for this process arises from three main factors: hydrogen bonding between the guanines in a plane, π π interaction between the guanines in adjacent planes and charge – charge interaction between partially negative oxygen of guanines and cations that typically sit in the octahedral position between the stacks (5-7). The monovalent cations such as K+ and Na+ at a physiological temperature and pH stabilize G-quadruplex by coordinating the carbonyl group of guanine at the center of G-tetrad core (5, 8). It has been estimated that there are more than 376,000 potential quadruplex sequences found in number of important biological processes (9). Intramolecular G-quadruplexes formed by single-stranded DNA are currently under intensive research due to their potential formation in telomeres and promoter sequences (10, 11). The present review reports the G-quadruplexes formed in human telomeres and proto-oncogenes.