期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2006
卷号：103
期号：31
页码：11497-11502
DOI：10.1073/pnas.0604939103
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The DNA abnormality found in 98% of Friedreich's ataxia (FRDA) patients is the unstable hyperexpansion of a GAA{middle dot}TTC triplet repeat in the first intron of the frataxin gene. Expanded GAA{middle dot}TTC repeats result in decreased transcription and reduced levels of frataxin protein in affected individuals. [beta]-Alanine-linked pyrrole-imidazole polyamides bind GAA{middle dot}TTC tracts with high affinity and disrupt the intramolecular DNA{middle dot}DNA-associated region of the sticky-DNA conformation formed by long GAA{middle dot}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{middle dot}TTC repeats or by chromatin opening.
