Suppression of Gene Expression by G-Quadruplexes in Open Reading Frames Depends on G-Quadruplex Stability

摘要

Guanine-rich (G-rich) sequences of DNA form G-quadru-plexes, a non-canonical structure stabilized by stacked G-quartets consisting of four guanine bases that interact through Hoogsteen-type hydrogen bonds. G-quadruplexes have been studied from physical, chemical, and biological points of view because of their unique structure and stability under physiological conditions.] The best characterized G-quad-ruplex is that formed by the G-rich repeats of DNA at the ends of chromosomes, termed telomeres. Because the telomere performs essential functions in chromosome maintenance and protection, the potential for G-quadruplex formation in telomere regions has potential importance for therapies. G-rich RNA can also form G-quadruplexes; these structures have higher melting temperatures than those formed by equivalent DNA sequences. The high thermodynamic stability of RNA G-quadruplexes may affect various biological processes such as replication, transcription, and post-transcriptional editing. Bioinformatic studies have revealed that sequences with quadruplex-forming potential (SQFPs) are found in the 5' untranslated regions (UTRs) of oncogene mRNAs. Because protein expression from these mRNAs decreases upon addition of G-quadruplex ligands and increases when mutations that disrupt the G-quadruplex formation are incorporated, it is assumed that the quadruplex-forming sequences in the 5' UTRs regulate protein-expression levels through formation of RNA G-quadruplexes.