Spt4 is selectively required for transcription of extended trinucleotide repeats

Cell
Chia-Rung LiuTzu-Hao Cheng

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.

References

Apr 14, 1999·Proceedings of the National Academy of Sciences of the United States of America·E ScherzingerE E Wanker
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·A KazantsevD Housman
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·S Krobitsch, S Lindquist
Jun 9, 2000·Annual Review of Neuroscience·H Y Zoghbi, H T Orr
Nov 25, 2000·Human Molecular Genetics·F TrettelM E MacDonald
Feb 13, 2001·Experimental Neurology·M E EhrlichE Cattaneo
Jun 19, 2001·The EMBO Journal·S R Biggar, G R Crabtree
Jun 12, 2002·The Journal of Cell Biology·Anatoli B MeriinMichael Y Sherman
Jan 30, 2003·The EMBO Journal·Ana G RondónAndrés Aguilera
Oct 4, 2003·Cytogenetic and Genome Research·B A Lenzmeier, C H Freudenreich
Jun 9, 2006·Methods : a Companion to Methods in Enzymology·Chih-Yen KingHsiang-Yu Chang
Jul 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Martin L DuennwaldSusan Lindquist
Sep 20, 2006·Proceedings of the National Academy of Sciences of the United States of America·Vladimir VoynovGerald R Fink
Jan 2, 2007·Nature Chemical Biology·Hemant VarmaBrent R Stockwell
Jun 3, 2008·Nature Methods·Ali MortazaviBarbara Wold
Jun 28, 2008·Biochimica Et Biophysica Acta·Sarah HandsAndreas Wyttenbach
Oct 3, 2008·Genome Biology·Nicole Cloonan, Sean M Grimmond
Dec 20, 2008·Journal of Neurochemistry·Yu ZhangRobert M Friedlander
Dec 18, 2009·Journal of Neurochemistry·Jacek LichotaTorben Moos
Jan 14, 2010·Current Protocols in Molecular Biology·Ugrappa NagalakshmiMichael Snyder
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Yunfu LinMarek Napierala

❮ Previous
Next ❯

Citations

May 24, 2013·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Barbara CalaminiLinda S Kaltenbach
Jun 19, 2013·Trends in Biochemical Sciences·John Labbadia, Richard I Morimoto
Sep 13, 2013·Chemical Reviews·Finn Werner
Aug 3, 2013·Cell Death & Disease·R NalavadeS Krauss
Jan 1, 2013·Nucleic Acids Research·Boris P BelotserkovskiiPhilip C Hanawalt
May 24, 2013·Genes & Development·Edwin Smith, Ali Shilatifard
Dec 5, 2012·PLoS Genetics·Agathi-Vasiliki GoulaKarine Merienne
Jul 16, 2015·Journal of Neurogenetics·Chia-Rung Liu, Tzu-Hao Cheng
Mar 24, 2015·The Tohoku Journal of Experimental Medicine·Shunchang SunHuiwen Song
Aug 29, 2014·Movement Disorders : Official Journal of the Movement Disorder Society·Neil Aronin, Marian DiFiglia
Sep 18, 2012·Biochimica Et Biophysica Acta·Grant A Hartzog, Jianhua Fu
Aug 12, 2014·Biochemical Society Transactions·Matthias GrohNatalia Gromak
May 23, 2014·Nucleic Acids Research·Agnieszka Fiszer, Wlodzimierz J Krzyzosiak
May 7, 2016·Nature Reviews. Neuroscience·Aaron R HaeuslerJeffrey D Rothstein
Nov 26, 2014·PloS One·Beatriz A SantillanJohn H Wilson
Jun 13, 2016·Molecular Genetics and Genomics : MGG·Makoto K ShimadaTadashi Imanishi
Jul 5, 2016·Protein Science : a Publication of the Protein Society·Amanda J BlytheAlice Vrielink
Aug 16, 2016·Science·Sarah Mizielinska, Adrian M Isaacs
Sep 14, 2013·ACS Chemical Biology·Leslie A CoonrodJ Andrew Berglund
Nov 8, 2013·Journal of Biomolecular Screening·Jonathan BardIgnacio Munoz-Sanjuan
Jun 3, 2017·Expert Opinion on Drug Discovery·Laura De ContiMarco Baralle
Jun 24, 2017·Human Molecular Genetics·Mercedes PrudencioChristopher D Link
Nov 21, 2017·PLoS Genetics·Andrea SilvaEulàlia de Nadal
Aug 31, 2017·Acta Neuropathologica Communications·Kushal J Rohilla, Keith T Gagnon
Mar 5, 2020·Wiley Interdisciplinary Reviews. RNA·Michael TellierShona Murphy
Apr 18, 2017·Orphanet Journal of Rare Diseases·Binbin Chen, Russ B Altman
Sep 15, 2018·The Journal of Biological Chemistry·John Douglas ClearyLaura P W Ranum
Aug 17, 2020·Nature Reviews. Neurology·Sarah J TabriziEdward J Wild
Jan 18, 2017·Cold Spring Harbor Perspectives in Medicine·Margaret M P Pearce, Ron R Kopito
Sep 29, 2018·Nature Communications·Andreas NeuederGillian P Bates
Feb 16, 2021·Current Neurology and Neuroscience Reports·Ling Pan, Andrew Feigin
Mar 11, 2021·Molecular Cell·Livia CaizziPatrick Cramer
Aug 1, 2020·Progress in Retinal and Eye Research·Michael P FautschAlice E Davidson
Sep 29, 2020·Journal of Molecular Biology·Tim-Michael Decker
May 11, 2021·Frontiers in Cellular Neuroscience·Daniel A SolomonSarah Mizielinska
Jun 3, 2021·Human Molecular Genetics·Leeanne McGurkNancy M Bonini

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