title: Bidirectional transcription of trinucleotide repeats: roles for excision repair.
abstract: Genomic instability at repetitive DNA regions in cells of the nervous system leads to a number of neurodegenerative 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 syndrome, 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 pathophysiology. 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, splicing, gene silencing, and chemical modification of DNAs. Paradoxically, however, some of the same effects are observed on both the expanded TNR gene and on its normal gene counterpart. In this review, we discuss the possible normal and abnormal effects of bidirectional transcription on trinucleotide repeat instability, the role of DNA repair in causing, preventing, or maintaining methylation, and chromatin environment of TNR genes.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Budworth
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004195:Disease Models, Animal; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology; D020868:Gene Silencing; D042822:Genomic Instability; D006801:Humans; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D002843:Chromatin; D004247:DNA
keywords: Bidirectional transcription; Coding; Excision repair; Neurodegenerative; RNA transcript; Trinucleotide