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Non-B DNA Conformations Formed by Long Repeating Tracts of Myotonic Dystrophy Type 1, Myotonic Dystrophy Type 2, and Friedreich's Ataxia Genes, Not the Sequences per se, Promote Mutagenesis in Flanking Regions*

M. Wojciechowska,M. Napierala,J. E. Larson,R. Wells

Published 2006 in Journal of Biological Chemistry

ABSTRACT

The expansions of long repeating tracts of CTG·CAG, CCTG·CAGG, and GAA·TTC are integral to the etiology of myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), and Friedreich's ataxia (FRDA). Essentially all studies on the molecular mechanisms of this expansion process invoke an important role for non-B DNA conformations which may be adopted by these repeat sequences. We have directly evaluated the role(s) of the repeating sequences per se, or of the non-B DNA conformations formed by these sequences, in the mutagenic process. Studies in Escherichia coli and three types of mammalian (COS-7, CV-1, and HEK-293) fibroblast-like cells revealed that conditions which promoted the formation of the non-B DNA structures enhanced the genetic instabilities, both within the repeat sequences and in the flanking sequences of up to ∼4 kbp. The three strategies utilized included: the in vivo modulation of global negative supercoil density using topA and gyrB mutant E. coli strains; the in vivo cleavage of hairpin loops, which are an obligate consequence of slipped-strand structures, cruciforms, and intramolecular triplexes, by inactivation of the SbcC protein; and by genetic instability studies with plasmids containing long repeating sequence inserts that do, and do not, adopt non-B DNA structures in vitro. Hence, non-B DNA conformations are critical for these mutagenesis mechanisms.

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