Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 31, Pages 11497-11502Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0604939103
Keywords
gene regulation; triplet repeat expansion; frataxin
Categories
Funding
- NIEHS NIH HHS [R01 ES011347, ES11347] Funding Source: Medline
- NIGMS NIH HHS [GM27681, R01 GM027681, R37 GM027681] Funding Source: Medline
- NINDS NIH HHS [R21 NS048989, NS37554, NS048989] Funding Source: Medline
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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.
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