Bidirectional transcription of trinucleotide repeats_ roles for excision repair.pdf

B r H L A A K B T E N C R 1 a w t o o T “ e h a h r h p r 1 hDNA Repair 12 (2013) 672– 684 Contents lists available at SciVerse ScienceDirect DNA Repair j ourna l ho me p age : www.elsev ier .com/ locate /dnarepai r idirectional transcription of trinucleotide repeats: Roles for excision epair elen Budworth, Cynthia T. McMurray ? ife Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA a r t i c l e i n f o rticle history: vailable online 11 May 2013 eywords: idirectional transcription rinucleotide xcision repair eurodegenerative oding NA transcript a b s t r a c t Genomic instability at repetitive DNA regions in cells of the nervous system leads to a number of neurode- generative and neuromuscular diseases, including those with an expanded trinucleotide repeat (TNR) tract at or nearby an expressed gene. Expansion causes disease when a particular base sequence is repeated beyond the normal range, interfering with the expression or properties of a gene product. Disease severity and onset depend on the number of repeats. As the length of the repeat tract grows, so does the size of the successive expansions and the likelihood of another unstable event. In fragile X syn- drome, for example, CGG repeat instability and pathogenesis are not typically observed below tracts of roughly 50 repeats, but occur frequently at or above 55 repeats, and are virtually certain above 100–300 repeats. Recent evidence points to bidirectional transcription as a new aspect of TNR instability and pathophy- siology. Bidirectional transcription of TNR genes produces novel proteins and/or regulatory RNAs that influence both toxicity and epigenetic changes in TNR promoters. Bidirectional transcription of the TNR tract appears to influence aspects of its stability, gene processing, spli