Published online 20 February 2004
Nucleic Acids Research, 2004, Vol. 32, No. 3 1224-1231
© 2004 Oxford University Press
Length-dependent structure formation in Friedreich ataxia (GAA)n·(TTC)n repeats at neutral pH
Institute of Biosciences and Technology, Texas A&M University System Health Sciences Center, Houston, TX 77030, USA, 1 School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA, 2 Department of Biochemistry and Molecular Biology and Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA and 3 Department of Neurology, The University of Texas Medical Branch, Galveston, TX 77555, USA
*To whom correspondence should be addressed. Tel: +1 713 677 7675; Fax: +1 713 677 7689; Email: vpotaman{at}ibt.tamushsc.edu
More than 15 human genetic diseases have been associated with the expansion of trinucleotide DNA repeats, which may involve the formation of non-duplex DNA structures. The slipped-strand nucleation of duplex DNA within GC-rich trinucleotide repeats may result in the changes of repeat length; however, such a mechanism seems less likely for the AT-rich (GAA)n·(TTC)n repeats. Using two-dimensional agarose gels, chemical probing and atomic force microscopy, we characterized the formation of non-B-DNA structures in the Friedreich ataxia-associated (GAA)n·(TTC)n repeats from the FRDA gene that were cloned with flanking genomic sequences into plasmids. For the normal genomic repeat length (n = 9) our data are consistent with the formation of a very stable protonated intramolecular triplex (H-DNA). Its stability at pH 7.4 is likely due to the high proportion of the T·A·T triads which form within the repeats as well as in the immediately adjacent AT-rich sequences with a homopurine· homopyrimidine bias. At the long normal repeat length (n = 23), a family of H-DNAs of slightly different sizes has been detected. At the premutation repeat length (n = 42) and higher negative supercoiling, the formation of a single H-DNA structure becomes less favorable and the data are consistent with the formation of a bi-triplex structure.
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