Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes.

Autor:	Deng N; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305., Wu YY; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, 11529, Taiwan.; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Feng Y; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305., Hsieh WC; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Song JS; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, 35053, Taiwan., Lin YS; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Tseng YH; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Liao WJ; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Chu YF; Department of Life Science and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Liu YC; Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Chang EC; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Liu CR; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Sheu SY; Department of Life Science and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Su MT; Department of Life Science, National Taiwan Normal University, Taipei, 11677, Taiwan., Kuo HC; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, 11529, Taiwan., Cohen SN; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305., Cheng TH; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, 11529, Taiwan.; Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Aug 09; Vol. 119 (32), pp. e2204779119. Date of Electronic Publication: 2022 Aug 01.
DOI:	10.1073/pnas.2204779119
Abstrakt:	Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene ( HTT ), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.
Databáze:	MEDLINE
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