Hsp90 globally targets paused RNA polymerase to regulate gene expression in response to environmental stimuli

Cell
Ritwick SawarkarRenato Paro

Abstract

The molecular chaperone Heat shock protein 90 (Hsp90) promotes the maturation of several important proteins and plays a key role in development, cancer progression, and evolutionary diversification. By mapping chromatin-binding sites of Hsp90 at high resolution across the Drosophila genome, we uncover an unexpected mechanism by which Hsp90 orchestrates cellular physiology. It localizes near promoters of many coding and noncoding genes including microRNAs. Using computational and biochemical analyses, we find that Hsp90 maintains and optimizes RNA polymerase II pausing via stabilization of the negative elongation factor complex (NELF). Inhibition of Hsp90 leads to upregulation of target genes, and Hsp90 is required for maximal activation of paused genes in Drosophila and mammalian cells in response to environmental stimuli. Our findings add a molecular dimension to the chaperone's functionality with wide ramifications into its roles in health, disease, and evolution.

References

Nov 1, 1992·Genes & Development·C GiardinaJ T Lis
Jan 1, 1988·Annual Review of Genetics·S Lindquist, E A Craig
May 26, 1995·The Journal of Biological Chemistry·N F Marshall, D H Price
Dec 9, 1998·Nature·S L Rutherford, S Lindquist
Jun 16, 2001·Journal of Cellular Biochemistry·W D Cornwell, R B Kirkpatrick
Sep 13, 2001·The Journal of Biological Chemistry·D B RennerD H Price
Jun 22, 2002·Science·Brian C Freeman, Keith R Yamamoto
Jun 5, 2003·Genes & Development·Chwen-Huey WuDavid Gilmour
Jul 6, 2004·Nature Cell Biology·Ryuji HamamotoYusuke Nakamura
Jan 31, 2006·Developmental Biology·Knud NairzErnst Hafen
May 22, 2007·Annals of the New York Academy of Sciences·Paul WorkmanNeal Rosen
Nov 13, 2007·Nature Genetics·Ginger W MuseKaren Adelman
Feb 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·Monique FloerMark Ptashne
Mar 12, 2008·Molecular and Cellular Biology·Chanhyo LeeDavid S Gilmour
Sep 19, 2008·Genome Biology·Yong ZhangX Shirley Liu
Oct 17, 2008·Genes & Development·Martin Eilers, Robert N Eisenman
Jan 16, 2009·Proceedings of the National Academy of Sciences of the United States of America·Muhammad TariqRenato Paro
Mar 11, 2009·Methods : a Companion to Methods in Enzymology·David S Gilmour, Ruopeng Fan
May 22, 2009·Molecular Biology of the Cell·Justin M PareTom C Hobman
Oct 13, 2009·Proceedings of the National Academy of Sciences of the United States of America·Karen AdelmanInez Rogatsky
Dec 17, 2009·Biochimica Et Biophysica Acta·Pablo C Echeverria, Didier Picard
Jun 10, 2010·Nature Reviews. Molecular Cell Biology·Mikko TaipaleSusan Lindquist
Jul 24, 2010·Nature Reviews. Cancer·Jane TrepelLen Neckers
Sep 17, 2010·PLoS Genetics·Michael J Guertin, John T Lis
Oct 13, 2010·The Journal of Biological Chemistry·Luciano VozzoloAriberto Fassati
Oct 29, 2010·Genome Biology·Simon Anders, Wolfgang Huber
Dec 15, 2010·Current Protocols in Bioinformatics·Ben Langmead
Mar 25, 2011·American Journal of Physiology. Cell Physiology·Suxin LuoYong Xia
May 31, 2011·Nature Neuroscience·Ramendra N SahaSerena M Dudek

❮ Previous
Next ❯

Citations

Jan 5, 2013·Nature Structural & Molecular Biology·Gabriela ChiosisJill L Johnson
Jun 28, 2013·Retrovirology·Carine Van LintAlessandro Marcello
Jan 28, 2014·PLoS Computational Biology·Federico Comoglio, Renato Paro
Sep 27, 2013·PLoS Genetics·Gonzalo Millán-ZambranoSebastián Chávez
Apr 20, 2014·Cell and Tissue Research·Simon Friedensohn, Ritwick Sawarkar
Apr 8, 2014·Proceedings of the National Academy of Sciences of the United States of America·Ian AndersonAriberto Fassati
Apr 12, 2014·Parasitology·Victoria Gillan, Eileen Devaney
May 30, 2012·Nature Reviews. Genetics·Darren J Burgess
Jan 5, 2013·Trends in Cell Biology·Ritwick Sawarkar, Renato Paro
Jan 30, 2013·The FEBS Journal·Jared J Barrott, Timothy A J Haystead
Oct 31, 2014·Annals of Clinical and Translational Neurology·Isabella BordiMarco Salvetti
May 9, 2014·The New Phytologist·Despina SamakovliPolydefkis Hatzopoulos
Oct 10, 2015·Adipocyte·Judith ToneattoGraciela Piwien-Pilipuk
Jan 7, 2014·Biochimica Et Biophysica Acta·Alejandra G ErlejmanMario D Galigniana
Jul 18, 2015·Nature Reviews. Genetics·Marie-Anne Félix, Michalis Barkoulas
May 19, 2012·Developmental Cell·Mark L Siegal, Christine Rushlow
May 27, 2014·Biochemical and Biophysical Research Communications·Mellissa HicksJames DeWille
Jun 17, 2016·Molecular Biology of the Cell·Nidhi KhuranaSunanda Bhattacharyya
Jan 31, 2017·Nature Structural & Molecular Biology·Barbara HummelRitwick Sawarkar
Nov 13, 2015·International Journal of Molecular Sciences·Soung-Hun RohDavid J Tweardy
Jan 18, 2018·Antimicrobial Agents and Chemotherapy·Dora PosfaiEmily R Derbyshire
May 13, 2018·The Plant Journal : for Cell and Molecular Biology·Qian-Qian ZhangLei Ge
Nov 28, 2018·Journal of Molecular Endocrinology·Gauthier SchangDaniel J Bernard
Mar 11, 2018·Nature Communications·Marina E BorisovaPetra Beli
Jul 10, 2014·Parasitology·Jun Siong Low, Ariberto Fassati

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.