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. P-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.