CTG REPEATS ASSOCIATED WITH HUMAN GENETIC-DISEASE ARE INHERENTLY FLEXIBLE

The lengthening of tracts of CTG, CGG and GAA triplet repeats during p rogression of a pedigree has been associated with more than 12 human g enetic diseases, including fragile X syndrome, myotonic dystrophy and Friedreich's ataxia. These repetitive sequence elements have the poten tial to form alternative DNA secondary structures that may contribute to their instability. The alternative DNA secondary structures may med iate errors during DNA replication, repair or recombination of the tri plet repeat, leading to expansion. Here we show that DNA composed of p ure CTG or CGG repeats exhibits anomalously fast mobility on polyacryl amide gels, confirming a previous observation for DNA containing CTG a nd CGG triplet repeats flanked by mixed sequence DNA. Moreover, we sho w that even short tracts of duplex CTG repeats have an unusual helix s tructure. CTG repeats reduce overall curvature associated with phased A-tract or GGCC curves, but alone they do not introduce curvature into DNA. The reduction in curvature of phased A-tracts by CTG repeats is similar to that afforded by an interspersed flexible region associated with a (TT).(TT) mispair. CTG-containing DNAs exhibit a rapid rate of cyclization, consistent with a flexible helix. These results suggest that tracts of (CTG).(CAG) repeats are inherently flexible. In additio n, our results suggest that the unusual rapid electrophoretic mobility of CTG or CGG-containing DNA may be a consequence of an extended flex ible DNA chain. (C) 1998 Academic Press Limited.