Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics.
Guanine-rich DNA sequences can form G-quadruplexes stabilized by stacked G-G-G-G tetrads in monovalent cation-containing solution. The length and number of individual G-tracts and the length and sequence context of linker residues define the diverse topologies adopted by G-quadruplexes. The review highlights recent solution NMR-based G-quadruplex structures formed by the four-repeat human telomere in K(+) solution and the guanine-rich strands of c-myc, c-kit and variant bcl-2 oncogenic promoters, as well as a bimolecular G-quadruplex that targets HIV-1 integrase. Such structure determinations have helped to identify unanticipated scaffolds such as interlocked G-quadruplexes, as well as novel topologies represented by double-chain-reversal and V-shaped loops, triads, mixed tetrads, adenine-mediated pentads and hexads and snap-back G-tetrad alignments. The review also highlights the recent identification of guanine-rich sequences positioned adjacent to translation start sites in 5'-untranslated regions (5'-UTRs) of RNA oncogenic sequences. The activity of the enzyme telomerase, which maintains telomere length, can be negatively regulated through G-quadruplex formation at telomeric ends. The review evaluates progress related to ongoing efforts to identify small molecule drugs that bind and stabilize distinct G-quadruplex scaffolds associated with telomeric and oncogenic sequences, and outlines progress towards identifying recognition principles based on several X-ray-based structures of ligand-G-quadruplex complexes.
Patel
Dinshaw J
DJ
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. pateld@mskcc.org
Phan
Anh Tuân
AT
Kuryavyi
Vitaly
V
D020121:5' Untranslated Regions / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D042622:DNA Repeat Expansion; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D012313:RNA / Q000737:chemistry / Q000187:drug effects; D016615:Telomere / Q000737:chemistry*
D020121:5' Untranslated Regions; D012313:RNA; D004247:DNA