Cover Picture: Small Molecule Modulates Hairpin Structures in CAG Trinucleotide Repeats (ChemBioChem 11/2011)

Abstract

The cover picture shows the selective binding of a synthetic naphthyridine-azaquinolone (NA) ligand to a CAG/CAG-triad-containing DNA. In humans, unusual expansion of the trinucleotide repeat is associated with a number of severe neurodegenerative diseases, such as Huntington's disease, spinobulbar muscular atrophy, and spinocerebellar ataxia. The d(CAG)n expansion mutation in the Huntington gene results in the production of aberrant protein that leads to gradual damage to specific areas of the brain. Although the actual mechanism of repeat expansion remains uncertain, repeat instability of CAG/CTG might be related to the increased stability of an alternative DNA hairpin structure in the d(CAG) repeat sequences. On p. 1686 ff, K. Nakatani et al. show that NA stabilizes hairpin secondary structures on d(CAG)n repeats, which efficiently interferes with DNA replication by Taq polymerase and human DNA polymerase A. Considering the selective sequence preference, the use of NA would be valuable in understanding the features of the genetic instabilities of CAG/CTG repeat sequences in genomes.