G-Quadruplex DNA and RNA

Abstract

G-quadruplexes (G4s) have become one of the most exciting nucleic acid secondary structures. A noncanonical, four-stranded structure formed in guanine-rich DNA and RNA sequences, G-quadruplexes can readily form under physiologically relevant conditions and are globularly folded structures. DNA is widely recognized as a double-helical structure essential in genetic information storage. However, only~3% of the human genome is expressed in protein; RNA and DNA may form noncanonical secondary structures that are functionally important. G-quadruplexes are one such example which have gained considerable attention for their formation and regulatory roles in biologically significant regions, such as human telomeres, oncogene-promoter regions, replication initiation sites, and 5 0 -and 3 0 -untranslated region (UTR) of mRNA. They are shown to be a regulatory motif in a number of critical cellular processes including gene transcription, translation, replication, and genomic stability. G-quadruplexes are also found in nonhuman genomes, particularly those of human pathogens. Therefore, G-quadruplexes have emerged as a new class of molecular targets for drug development. In addition, there is considerable interest in the use of G-quadruplexes for biomaterials, biosensors, and biocatalysts. The First International Meeting on Quadruplex DNA was held in 2007, and the G-quadruplex field has been growing dramatically over the last decade. The methods used to study G-quadruplexes have been essential to the rapid progress in our understanding of this exciting nucleic acid secondary structure. G-quadruplexes have been found to form in specific human guanine-rich sequences with functional significance, such as telomeres, oncogene-promoter regions, and 5 0 -and 3 0 -untranslated region (UTR) of mRNA, as well as in nonhuman genomes. G-Quadruplexes in TelomeresThe first biologically relevant G-quadruplex was observed in telomeric DNA. Telomeres are specific DNA-protein complexes at the ends of linear chromosomes, providing protection against gene erosion from cell divisions, chromosomal nonhomologous end-joinings, and nuclease attacks [19][20][21]. Telomeric G-quadruplexes were first reported as novel intramolecular structures containing guanine-guanine base-pairs in single-stranded telomeric sequences of several organisms [22], and as guaninetetrads between hairpin loops of the Tetrahymena telomeric DNA [23]. The importance of monovalent cations in the stabilization of G-quadruplex structures was revealed by Williamson, Cech in their monovalent cation-induced square-planar G-quartet model using the Oxytricha and Tetrahymena telomeric DNA [14]. Human telomeres consist of tandem repeats of the hexanucleotide d (TTAGGG) n 5-10 kb in length, which terminate in a singlestranded 3 0 -overhang of 35-600 bases [24]. Telomeres of cancer cells do not shorten upon replication, mainly due to the activation of a reverse transcriptase, telomerase, that extends the telomeric sequence at the chromosome ends [25]. Telomerase is activated in 80-85% of hu...

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“…Polynucleotide secondary structures, known as G-quadruplexes, are composed of several guanine tetrads that form layers through π-π stacking. G-quadruplexes can form rapidly under the appropriate physiological conditions and interact with speci c proteins that have either a stabilizing or unfolding function (13). Many G-quadruplexes are located in guanine-rich RNA or DNA sequences, particularly in the promoter regions of oncogenes such as c-Myc (14).…”

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