Studies on biological significance of g quadruplex DNA

Abstract

DNA double helix is known to have conformational polymorphism such as A, B and Z forms. Apart from these, it has been found that Guanine-rich DNA sequences can adopt unusual foldback four-stranded DNA structures called ‘G-quadruplex’. A Gquadruplex structure is formed by two or more consecutive stacks of ‘G-tetrads’, which are the coplanar association of four guanines in a cyclic reverse Hoogsteen hydrogen bonding fashion. The consecutive stacks of G-tetrads in G-quadruplex structure are further stabilized by monovalent cations, especially potassium ions. The guanine-rich DNA sequences which can potentially form G-quadruplex motifs have been identified and characterized by different biophysical and biochemical methods to be present in the upstream promoter regions of proto-oncogenes such as c-MYC, c-JUN, c-KIT, c-MYB, c-REL, etc. and interestingly the 3’-telomeric sequence of many eukaryotes. It has been proposed that these structures in telomere ends play significant roles in chromosome end protection and stabilization. There are also enough circumstantial evidences for other biological roles played by these higher DNA corformations like, in replication, transcription regulation and recombination. Additional evidence of their existence and biological relevance comes from fact that these motifs are recognized by different classes of proteins, including transcription factors, nucleases, helicases, reverse transcriptases, etc. In line, G-quadruplex specific small molecules have also gained more attention than ever due to their therapeutic value as anticancer drugs for telomerase inhibition resulting from binding to G-quadruplex motifs within the human telomeres. Similar avenues have been explored by developing molecules which perturbed c-MYC expression by stabilizing the G-quadruplex motif present in c-MYC promoter region. Nevertheless, these small molecules are also bolstering the existence of G-quadruplex motif in-vivo.