Drosophila brakeless interacts with atrophin and is required for tailless-mediated transcriptional repression in early embryos.

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Complex gene expression patterns in animal development are generated by the interplay of transcriptional activators and repressors at cis-regulatory DNA modules (CRMs ). How repressors work is not well understood , but often involves interactions with co -repressors . We isolated mutations in the brakeless gene in a screen for maternal factors affecting segmentation of the Drosophila embryo . Brakeless , also known as Scribbler , or Master of thickveins , is a nuclear protein of unknown function . In brakeless embryos , we noted an expanded expression pattern of the Krüppel (Kr ) and knirps (kni ) genes . We found that Tailless-mediated repression of kni expression is impaired in brakeless mutants . Tailless and Brakeless bind each other in vitro and interact genetically . Brakeless is recruited to the Kr and kni CRMs , and represses transcription when tethered to DNA . This suggests that Brakeless is a novel co -repressor . Orphan nuclear receptors of the Tailless type also interact with Atrophin co -repressors . We show that both Drosophila and human Brakeless and Atrophin interact in vitro , and propose that they act together as a co -repressor complex in many developmental contexts . We discuss the possibility that human Brakeless homologs may influence the toxicity of polyglutamine-expanded Atrophin-1 , which causes the human neurodegenerative disease dentatorubral-pallidoluysian atrophy (DRPLA ).