title: DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich's ataxia.
abstract: 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. Beta-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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Burnett
authors.forename: Christian
authors.initials: C
authors.lastname: Melander
authors.forename: James W
authors.initials: JW
authors.lastname: Puckett
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Son
authors.forename: Robert D
authors.initials: RD
authors.lastname: Wells
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
mesh_terms: D002460:Cell Line; D005621:Friedreich Ataxia / Q000235:genetics*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D008024:Ligands; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D018911:Trinucleotide Repeats; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D008024:Ligands; D009757:Nylons; D000096923:Frataxin