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DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA·TTC repeats in Friedreich's ataxia

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. PMCID PMC1544198. https://resolver.caltech.edu/CaltechAUTHORS:BURpnas06

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[img] PDF (Fig. 6. Quantitative DNase I footprint analysis for polyamides FA3 and FA4 binding to a radiolabeled (GAA•TTC)6 PCR product...) - Supplemental Material
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[img] PDF (Fig. 7. DNase I footprint analysis for polyamide FA1 binding to a radiolabeled (GAA•TTC)33 PCR product derived from plasmid pMP142 DNA...) - Supplemental Material
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[img] PDF (Fig. 8. Quantitative DNase I footprint analysis for polyamides FA1 and FA3 binding to a radiolabeled DNA containing a mismatch DNA sequence (5'-AGGAGGAGGTGGAGGAGGA-3'...) - Supplemental Material
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[img] PDF (Fig. 9. Quantitative DNase I footprint analysis for polyamide FA1-Bodipy conjugate binding to a radiolabeled (GAA•TTC)6 PCR product) - Supplemental Material
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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. 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1544198/PubMed CentralArticle
http://www.pnas.org/content/103/31/11497/suppl/DC1PublisherSupporting Information
https://doi.org/10.1073/pnas.0604939103DOIUNSPECIFIED
https://doi.org/10.1073/pnas.0604939103DOIUNSPECIFIED
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
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.
Funders:
Funding AgencyGrant Number
NIHNS-048989
NIHGM-27681
NIHNS-37554
NIHES-11347
Friedreich’s Ataxia Research AllianceUNSPECIFIED
Seek-a-Miracle FoundationUNSPECIFIED
Subject Keywords:gene regulation; triplet repeat expansion; frataxin
Issue or Number:31
PubMed Central ID:PMC1544198
Record Number:CaltechAUTHORS:BURpnas06
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:BURpnas06
Official Citation:Ryan Burnett, Christian Melander, James W. Puckett, Leslie S. Son, Robert D. Wells, Peter B. Dervan, and Joel M. Gottesfeld DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA·TTC repeats in Friedreich's ataxia PNAS 2006 103 (31) 11497-11502; published ahead of print July 20, 2006, doi:10.1073/pnas.0604939103
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8079
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Jul 2007
Last Modified:26 Nov 2019 11:15

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