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Nucleic Acids Research, 2000, Vol. 28, No. 24 4930-4937
© 2000 Oxford University Press

Alleviating transcript insufficiency caused by Friedreich’s ataxia triplet repeats

Ed Grabczyk* and Karen Usdin

Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA

Expanded GAA·TTC trinucleotide repeats in intron 1 of the frataxin gene cause Friedreich’s ataxia (FRDA) by reducing frataxin mRNA levels. Insufficient frataxin, a nuclear encoded mitochondrial protein, leads to the progressive neurodegeneration and cardiomyopathy characteristic of FRDA. Previously we demonstrated that long GAA·TTC tracts impede transcription elongation in vitro and provided evidence that the impediment results from an intramolecular purine·purine·pyrimidine DNA triplex formed behind an advancing RNA polymerase. Our model predicts that inhibiting formation of this triplex during transcription will increase successful elongation through GAA·TTC tracts. Here we show that this is the case. Oligodeoxyribonucleotides designed to block particular types of triplex formation provide specific and concentration-dependent increases in full-length transcript. In principle, therapeutic agents that selectively interfere with triplex formation could alleviate the frataxin transcript insufficiency caused by pathogenic FRDA alleles.

* To whom correspondence should be addressed at: Building 8, Room 202, 8 Center Drive MSC 0830, National Institutes of Health, Bethesda, MD 20892-0830, USA. Tel: +1 301 594 5259; Fax: +1 301 402 0053; Email: grabczyk{at}helix.nih.gov


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