Author/Editor		Zhai, Weiguo; Jeong, Hyunkyung; Cui, Libin; Krainc, Dimitri; Tjian, Robert
Title		In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets
Type		članek
Source		Cell
Vol. and No.		Letnik 123, št. 7
Publication year		2005
Volume		str. 1241-53
Language		eng
Abstract		Transcriptional dysregulation has emerged as a potentially important pathogenic mechanism in Huntington's disease, a neurodegenerative disorder associated with polyglutamine expansion in the huntingtin (htt) protein. Here, we report the development of a biochemically defined in vitro transcription assay that is responsive to mutant htt. We demonstrate that both gene-specific activator protein Sp1 and selective components of the core transcription apparatus, including TFIID and TFIIF, are direct targets inhibited by mutant htt in a polyglutamine-dependent manner. The RAP30 subunit of TFIIF specifically interacts with mutant htt both in vitro and in vivo to interfere with formation of the RAP30-RAP74 native complex. Importantly, overexpression of RAP30 in cultured primary striatal cells protects neurons from mutant htt-induced cellular toxicity and alleviates the transcriptional inhibition of the dopamine D2 receptor gene by mutant htt. Our results suggest a mutant htt-directed repression mechanism involving multiple specific components of the basal transcription apparatus.
Descriptors		ANIMALS BIOLOGICAL ASSAY COS CELLS CELL-FREE SYSTEM CELLS, CULTURED CERCOPITHECUS AETHIOPS MICE MUTATION NERVE TISSUE PROTEINS NEURONS NUCLEAR PROTEINS PROTEIN BINDING RATS RECEPTORS, DOPAMINE D2 TRANSCRIPTION FACTORS TRANSCRIPTION FACTORS, TFII TRANSCRIPTION, GENETIC