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J Biol Chem, Vol. 273, Issue 23, 14588-14595, June 5, 1998

Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replication in Vivo

Keiichi OhshimaDagger , Laura MonterminiDagger , Robert D. Wellsparallel , and Massimo PandolfoDagger **Dagger Dagger

From the Dagger  Centre de Recherche Louis-Charles Simard, C.H.U.M., Campus Notre-Dame, 1560 rue Sherbrooke est, Montréal, Québec H2L 4M1, Canada, the parallel  Institute of Biosciences and Technology, Center for Genome Research, Department of Biochemistry and Biophysics, Texas A&M University, Texas Medical Center, Houston, Texas 77030-3303, the ** Department of Medicine, Université de Montréal, Montréal, Québec H2L 4M1, Canada, and the Dagger Dagger  Departments of Neurology and Neurosurgery, McGill University, Montréal, Québec H3A 2B4, Canada

Friedreich ataxia (FRDA) is associated with the expansion of a GAA·TTC triplet repeat in the first intron of the frataxin gene, resulting in reduced levels of frataxin mRNA and protein. To investigate the mechanisms by which the intronic expansion produces its effect, GAA·TTC repeats of various lengths (9 to 270 triplets) were cloned in both orientations in the intron of a reporter gene. Plasmids containing these repeats were transiently transfected into COS-7 cells. A length- and orientation-dependent inhibition of reporter gene expression was observed. RNase protection and Northern blot analyses showed very low levels of mature mRNA when longer GAA repeats were transcribed, with no accumulation of primary transcript. Replication of plasmids carrying long GAA·TTC tracts (~250 triplets) was greatly inhibited in COS-7 cells compared with plasmids carrying (GAA·TTC)9 and (GAA·TTC)90. Replication inhibition was five times greater for the plasmid whose transcript contains (GAA)230 than for the plasmid whose transcript contains (UUC)270. Our in vivo investigation revealed that expanded GAA·TTC repeats from intron I of the FRDA gene inhibit transcription rather than post-transcriptional RNA processing and also interfere with replication. The molecular basis for these effects may be the formation of non-B DNA structures.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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