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Spt4 is selectively required for transcription of extended trinucleotide repeats.
Liu, Chia-Rung; Chang, Chuang-Rung; Chern, Yijuang; Wang, Tzu-Han; Hsieh, Wen-Chieh; Shen, Wen-Chuan; Chang, Chi-Yuan; Chu, I-Chieh; Deng, Ning; Cohen, Stanley N; Cheng, Tzu-Hao.
Afiliación
  • Liu CR; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei, Taiwan, Republic of China.
Cell ; 148(4): 690-701, 2012 Feb 17.
Article en En | MEDLINE | ID: mdl-22341442
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Saccharomyces cerevisiae / Transcripción Genética / Proteínas Nucleares / Repeticiones de Trinucleótidos / Proteínas de Saccharomyces cerevisiae / Factores de Elongación Transcripcional / Proteínas de Unión al ADN / Neuronas Límite: Animals / Humans Idioma: En Revista: Cell Año: 2012 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Saccharomyces cerevisiae / Transcripción Genética / Proteínas Nucleares / Repeticiones de Trinucleótidos / Proteínas de Saccharomyces cerevisiae / Factores de Elongación Transcripcional / Proteínas de Unión al ADN / Neuronas Límite: Animals / Humans Idioma: En Revista: Cell Año: 2012 Tipo del documento: Article País de afiliación: China