DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA·TTC repeats in Friedreich's ataxia

The DNA abnormality found in 98% of Friedreich's ataxia (FRDA) patients is the unstable hyperexpansion of a GAA·TTC triplet repeat in the first intron of the frataxin gene. Expanded GAA·TTC repeats result in decreased transcription and reduced levels of frataxin protein in affected individuals. β-Alanine-linked pyrrole–imidazole polyamides bind GAA·TTC tracts with high affinity and disrupt the intramolecular DNA·DNA-associated region of the sticky-DNA conformation formed by long GAA·TTC repeats. Fluorescent polyamide-Bodipy conjugates localize in the nucleus of a lymphoid cell line derived from a FRDA patient. The synthetic ligands increase transcription of the frataxin gene in cell culture, resulting in increased levels of frataxin protein. DNA microarray analyses indicate that a limited number of genes are significantly affected in FRDA cells. Polyamides may increase transcription by altering the DNA conformation of genes harboring long GAA·TTC repeats or by chromatin opening