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. 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.
Burnett
Ryan
R
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Melander
Christian
C
Puckett
James W
JW
Son
Leslie S
LS
Wells
Robert D
RD
Dervan
Peter B
PB
Gottesfeld
Joel M
JM
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
D033862:Iron-Binding Proteins; D008024:Ligands; D009757:Nylons; D000096923:Frataxin