Burnett, Ryan and Melander, Christian and Puckett, James W. and Son, Leslie S. and Wells, Robert D. and Dervan, Peter B. and Gottesfeld, Joel M. (2006) DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA·TTC repeats in Friedreich's ataxia. Proceedings of the National Academy of Sciences of the United States of America, 103 (31). pp. 11497-11502. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:BURpnas06
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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. 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.
|Additional Information:||© 2006 by the National Academy of Sciences. Contributed by Peter B. Dervan, June 16, 2006. Published online before print July 20, 2006, 10.1073/pnas.0604939103. We thank Malcolm Wood for assistance with deconvolution microscopy, Steve Head for statistical analysis of microarray data, and members of the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology for technical assistance and data analysis. This work was supported by National Institutes of Health Grants NS048989 (to J.M.G.), GM27681 (to P.B.D.), and NS37554 and ES11347 (to R.D.W.); the Friedreich’s Ataxia Research Alliance; and the Seek-a-Miracle Foundation (Muscular Dystrophy Association). Data deposition: The microarray data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE5040). Conflict of interest statement: No conflicts declared.|
|Subject Keywords:||gene regulation; triplet repeat expansion; frataxin|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||30 Jul 2007|
|Last Modified:||26 Dec 2012 09:36|
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