Journal
FASEB JOURNAL
Volume 22, Issue 6, Pages 1625-1634Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.07-097857
Keywords
sticky DNA; GAA; TTC; transcription silencing; non-B DNA conformations; genetic instability; polyamides
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Funding
- NIEHS NIH HHS [ES11347] Funding Source: Medline
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES011347] Funding Source: NIH RePORTER
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Friedreich ataxia, the most common inherited ataxia, is caused by the transcriptional silencing of the FXN gene, which codes for the 210 amino acid frataxin, a mitochondrial protein involved in iron-sulfur cluster biosynthesis. The expansion of the GAA center dot TTC tract in intron 1 to as many as 1700 repeats elicits the transcriptional silencing by the formation of non-B DNA structures (triplexes or sticky DNA), the formation of a persistent DNA center dot RNA hybrid, or heterochromatin formation. The triplex (sticky DNA) adopted by the long repeat sequence also elicits profound mutagenic, genetic instability, and recombination behaviors. Early stage therapeutic investigations involving polyamides or histone deacetylase inhibitors are being pursued. Friedreich ataxia may be one of the most thoroughly studied hereditary neurological disease from a pathophysiological standpoint.
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