Triplet repeat-derived siRNAs enhance RNA-mediated toxicity in a drosophila model for myotonic dystrophy

More than 20 human neurological and neurodegenerative diseases are caused by simple dna repeat expansions; among these,non-coding ctg repeat expansions are the basis of myotonic dystrophy (dm1). recent work,however,has also revealed that many human genes have anti-sense transcripts,raising the possibility that human trinucleotide expansion diseases may be comprised of pathogenic activities due both to a sense expanded-repeat transcript and to an anti-sense expanded-repeat transcript. we established a drosophila model for dm1 and tested the role of interactions between expanded ctg transcripts and expanded cag repeat transcripts. these studies revealed dramatically enhanced toxicity in flies co-expressing ctg with cag expanded repeats. expression of the two transcripts led to novel pathogenesis with the generation of dcr-2 and ago2-dependent 21-nt triplet repeat-derived sirnas. these small rnas targeted the expression of cag-containing genes,such as ataxin-2 and tata binding protein (tbp),which bear long cag repeats in both fly and man. these findings indicate that the generation of triplet repeat-derived sirnas may dramatically enhance toxicity in human repeat expansion diseases in which anti-sense transcription occurs. © 2011 yu et al.