Molecular Biology

Un-ruley Translation

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Science  14 Jan 2011:
Vol. 331, Issue 6014, pp. 127
DOI: 10.1126/science.331.6014.127-a

Several inherited neurodegenerative diseases are referred to as “triplet repeat disorders” because they are caused by the aberrant expansion of three consecutive nucleotides near or within specific disease genes. CAG and CTG repeats, for example, are found in certain forms of myotonic dystrophy, spinocerebellar ataxia, and Huntington's disease. Numerous hypotheses have been proposed to explain how these DNA repeats contribute to disease pathogenesis, including toxic or inhibitory interactions of the expanded encoded RNA or protein with the normal protein.

Adding further complexity to the issue is the new discovery that triplet repeat sequences do not always obey canonical rules of protein synthesis. Studying RNA constructs harboring expanded CAG and CTG repeats, Zu et al. found that the repeats were translated in all three reading frames, thereby generating aberrant proteins containing polyglutamine, polyalanine, or polyserine. Synthesis of these proteins occurred in the absence of an ATG start codon (normally a prerequisite for translational initiation), possibly because the repeats form hairpin structures that allow initiation to occur at suboptimal sites. These results suggest that such proteins may play a role in the pathogenesis of CAG and CTG expansion disorders and, in a more general sense, they raise the possibility that other repeat sequences in the genome once thought to be silent may in fact be translated into proteins.

Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1013343108 (2010).

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