There has been much current interest in the long-range oxidative damage to DNA through the DNA duplex caused by one-electron oxidations. 1 Hole (radical cation) migration through the DNA duplex has been suggested to play a crucial role in mutagenesis and carcinogenesis caused by carcinogenic agents, ionizing radiation, and high-intensity laser irradiation. 1,2 As is well-known, guanine (G) is the most easily oxidized base, 3 and the electron-loss center created in duplex DNA ultimately ends up at G residues via hole migration through the DNA duplex. Several years ago, we demonstrated both experimentally and by ab initio calculations that 5′-G residues of 5′-GG-3′ steps in B-form DNA are the most easily oxidized due to the GG stacks and can act as thermodynamic sinks in hole migration across the DNA π stack. 4 We also demonstrated that the highest occupied molecular orbital (HOMO) of a GG stack is especially high in energy and concentrated on the 5′-G. 4b Thereafter, examples of 5′-G selective oxidations have been reported in many different systems. These include (i) photooxidation using different types of DNA-binding agents such as Rh(III)-metallointercalators, 1a-c,f substituted anthraquinones, 1d,e,5 riboflavin, 6 naphthalimide derivatives, 4 a p-cyano-substituted benzophenone, 7 and pterins; 8 (ii) chemical oxidation by Ru(III)-metallointercalators 1c,9 and Ni(II)ligand/sulfite system; 10 (iii) two-photon photoionization of DNA with a high-intensity laser pulse (266 nm); 11 and (iv) direct irradiation with a powerful 193-nm excimer laser. 12 Notably, the 5′-G selectivity of 5′-GG-3′ steps is irrelevant to the structural
DNA trinucleotide repeats, particularly CXG, are common within the human genome. However, expansion of trinucleotide repeats is associated with a number of disorders, including Huntington disease, spinobulbar muscular atrophy and spinocerebellar ataxia. In these cases, the repeat length is known to correlate with decreased age of onset and disease severity. Repeat expansion of (CAG)n, (CTG)n and (CGG)n trinucleotides may be related to the increased stability of alternative DNA hairpin structures consisting of CXG-CXG triads with X-X mismatches. Small-molecule ligands that selectively bound to CAG repeats could provide an important probe for determining repeat length and an important tool for investigating the in vivo repeat extension mechanism. Here we report that napthyridine-azaquinolone (NA, 1) is a ligand for CAG repeats and can be used as a diagnostic tool for determining repeat length. We show by NMR spectroscopy that binding of NA to CAG repeats induces the extrusion of a cytidine nucleotide from the DNA helix.
Here we have designed and synthesized ligands that specifically bind with high affinity (K(d) = 53 nM) to the guanine (G)-guanine mismatch, one of four types of single-nucleotide polymorphism (SNP). Detection of the G-G mismatch was performed by a surface plasmon resonance (SPR) assay using a sensor chip carrying the G-G specific ligand on its surface. The accuracy of the G-G mismatch detection by the SPR sensor was demonstrated by a marked SPR response obtained only for the DNA containing the G-G mismatch. DNAs containing G-A and G-T mismatches, as well as a fully matched duplex, produced only a weak response. Furthermore, this assay was found applicable for the detection of SNP existing in PCR amplification products of a 652-nucleotide sequence of the HSP70-2 gene.
DNA molecular glue is a small synthetic ligand that can adhere two single-stranded DNAs that do not spontaneously hybridize with each other. For reversible control of DNA hybridization by an external light stimulus, we have developed a photoswitchable molecular glue for DNA. The photoswitchable molecular glue, NCDA, consists of two guanine-recognizing naphthyridine moieties connected with a photochromic azobenzene unit. Azobenzene undergoes a reversible cis/trans isomerization by photoirradiation, which changes the relative orientations and positions of the naphthyridine moieties, resulting into photoswitching of NCDA binding to the DNA containing GG-mismatch. NCDA in the cis configuration binds to a GG-mismatch sequence and induces the formation of the DNA duplex. Using the photoswitchable binding property of NCDA, the hybridization event of two natural unmodified DNAs can be reversibly controlled by an external light stimulus.
In many repeat diseases, like Huntington’s disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound
N
aphthyridine-
A
zaquinolone (NA) that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as
en masse
contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independent of DNA replication, require transcription across the coding CTG strand, and arise by blocking repair of CAG slip-outs. NA-induced contractions depend upon active expansions driven by MutSβ. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat structure-specific DNA ligands are a novel avenue to contract expanded repeats.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.