title: Spt4 is selectively required for transcription of extended trinucleotide repeats.
abstract: Lengthy trinucleotide repeats encoding polyglutamine (polyQ) stretches characterize the variant proteins of Huntington's disease and certain other inherited neurological disorders. Using a phenotypic screen to identify events that restore functionality to polyQ proteins in S. cerevisiae, we discovered that transcription elongation factor Spt4 is required to transcribe long trinucleotide repeats located either in ORFs or nonprotein-coding regions of DNA templates. Mutation of SPT4 selectively decreased synthesis of and restored enzymatic activity to expanded polyQ protein without affecting protein lacking long-polyQ stretches. RNA-seq analysis revealed limited effects of Spt4 on overall gene expression. Inhibition of Supt4h, the mammalian ortholog of Spt4, reduced mutant huntingtin protein in neuronal cells and decreased its aggregation and toxicity while not altering overall cellular mRNA synthesis. Our findings identify a cellular mechanism for transcription through repeated trinucleotides and a potential target for countermeasures against neurological disorders attributable to expanded trinucleotide regions.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei, Taiwan, Republic of China.
authors.forename: Chia-Rung
authors.initials: CR
authors.lastname: Liu
authors.forename: Chuang-Rung
authors.initials: CR
authors.lastname: Chang
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
authors.forename: Tzu-Han
authors.initials: TH
authors.lastname: Wang
authors.forename: Wen-Chieh
authors.initials: WC
authors.lastname: Hsieh
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Shen
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chang
authors.forename: I-Chieh
authors.initials: IC
authors.lastname: Chu
authors.forename: Ning
authors.initials: N
authors.lastname: Deng
authors.forename: Stanley N
authors.initials: SN
authors.lastname: Cohen
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000378:metabolism*; D018911:Trinucleotide Repeats
chemical_list: D004268:DNA-Binding Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C080991:SPT4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C484413:Supt4h protein, mouse; D035602:Transcriptional Elongation Factors; C097188:polyglutamine