Topoisomerase 1 and single-strand break repair modulate transcription-induced CAG repeat contraction in human cells.

ABSTRACT: Expanded trinucleotide repeats are responsible for a number of neurodegenerative diseases, such as Huntington disease and myotonic dystrophy type 1. The mechanisms that underlie repeat instability in the germ line and in the somatic tissues of human patients are undefined. Using a selection assay based on contraction of CAG repeat tracts in human cells, we screened the Prestwick chemical library in a moderately high-throughput assay and identified 18 novel inducers of repeat contraction. A subset of these compounds targeted pathways involved in the management of DNA supercoiling associated with transcription. Further analyses using both small molecule inhibitors and small interfering RNA (siRNA)-mediated knockdowns demonstrated the involvement of topoisomerase 1 (TOP1), tyrosyl-DNA phospho

SUBMITTER: Hubert L 

PROVIDER: S-EPMC3147608 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature