In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets

Weiguo Zhai*, Hyunkyung Jeong, Libin Cui, Dimitri Krainc, Robert Tjian

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1241-1253
Number of pages13
JournalCell
Volume123
Issue number7
DOIs
StatePublished - Dec 29 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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