title: Functional genomics indicates yeast requires Golgi/ER transport, chromatin remodeling, and DNA repair for low dose DMSO tolerance.
abstract: Dimethyl sulfoxide (DMSO) is frequently utilized as a solvent in toxicological and pharmaceutical investigations. It is therefore important to establish the cellular and molecular targets of DMSO in order to differentiate its intrinsic effects from those elicited by a compound of interest. We performed a genome-wide functional screen in Saccharomyces cerevisiae to identify deletion mutants exhibiting sensitivity to 1% DMSO, a concentration standard to yeast chemical profiling studies. We report that mutants defective in Golgi/ER transport are sensitive to DMSO, including those lacking components of the conserved oligomeric Golgi (COG) complex. Moreover, strains deleted for members of the SWR1 histone exchange complex are hypersensitive to DMSO, with additional chromatin remodeling mutants displaying a range of growth defects. We also identify DNA repair genes important for DMSO tolerance. Finally, we demonstrate that overexpression of histone H2A.Z, which replaces chromatin-associated histone H2A in a SWR1-catalyzed reaction, confers resistance to DMSO. Many yeast genes described in this study have homologs in more complex organisms, and the data provided is applicable to future investigations into the cellular and molecular mechanisms of DMSO toxicity.
authors: Department of Nutritional Science and Toxicology, University of California Berkeley, CA, USA.
authors: Brandon D
authors: BD
authors: Gaytán
authors: Alex V
authors: AV
authors: Loguinov
authors: Vanessa Y
authors: VY
authors: De La Rosa
authors: Jan-Michael
authors: JM
authors: Lerot
authors: Chris D
authors: CD
authors: Vulpe
keywords: DMSO; chromatin; dimethyl sulfoxide; functional genomics; functional profiling; yeast
references: Mol Cell. 2011 May 20;42(4):536-49
references: 21596317
references: Biosci Rep. 1994 Dec;14(6):259-81
references: 7620078
references: Cancer Res. 1983 Dec;43(12 Pt 1):5718-24
references: 6416668
references: Toxicol Sci. 2013 Apr;132(2):347-58
references: 23358190
references: Mol Cell Biol. 2006 Aug;26(16):6117-29
references: 16880522
references: Cell. 2005 Oct 21;123(2):219-31
references: 16239141
references: Biochem Pharmacol. 2003 Apr 1;65(7):1035-41
references: 12663039
references: Handb Exp Pharmacol. 2006;(172):405-16
references: 16610368
references: J Cell Biol. 2011 Oct 17;195(2):323-40
references: 21987634
references: Biochem Cell Biol. 2009 Oct;87(5):799-815
references: 19898529
references: Nat Genet. 2002 Aug;31(4):400-4
references: 12134146
references: Cancer Res. 1978 Mar;38(3):841-9
references: 75063
references: Nature. 2007 Apr 12;446(7137):806-10
references: 17314980
references: PLoS One. 2010 Aug 12;5(8):e12143
references: 20711347
references: Nucleic Acids Res. 2010 Jul;38(13):e142
references: 20460461
references: Toxicol Appl Pharmacol. 2009 Dec 15;241(3):294-302
references: 19732783
references: Science. 2010 Jan 22;327(5964):425-31
references: 20093466
references: FEMS Yeast Res. 2013 Mar;13(2):200-18
references: 23157175
references: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10735-40
references: 8855249
references: Mol Cell Biol. 2008 Apr;28(7):2244-56
references: 18212056
references: Methods Mol Biol. 2012;910:55-69
references: 22821592
references: Science. 2004 Jan 16;303(5656):343-8
references: 14645854
references: Toxicol Sci. 2009 Oct;111(2):424-36
references: 19635755
references: J Mol Biol. 1974 Oct 15;89(1):137-62
references: 4475112
references: PLoS One. 2011;6(8):e24205
references: 21912624
references: Cryobiology. 2013 Feb;66(1):38-42
references: 23149044
references: PLoS One. 2012;7(1):e29798
references: 22253786
references: J Ind Microbiol Biotechnol. 2003 Jan;30(1):57-69
references: 12545388
references: Nature. 2002 Jul 25;418(6896):387-91
references: 12140549
references: BMC Bioinformatics. 2002 Nov 13;3:35
references: 12431279
references: Cell. 2003 Mar 7;112(5):725-36
references: 12628191
references: Hum Exp Toxicol. 2011 Oct;30(10):1701-9
references: 21339255
references: Mol Cell. 2009 Feb 13;33(3):335-43
references: 19217407