title: Genome-Wide Functional and Stress Response Profiling Reveals Toxic Mechanism and Genes Required for Tolerance to Benzo[a]pyrene in S. cerevisiae.
abstract: Benzo[a]pyrene (BaP) is a ubiquitous, potent, and complete carcinogen resulting from incomplete organic combustion. BaP can form DNA adducts but other mechanisms may play a role in toxicity. We used a functional toxicology approach in S. cerevisiae to assess the genetic requirements for cellular resistance to BaP. In addition, we examined translational activities of key genes involved in various stress response pathways. We identified multiple genes and processes involved in modulating BaP toxicity in yeast which support DNA damage as a primary mechanism of toxicity, but also identify other potential toxicity pathways. Gene ontology enrichment analysis indicated that DNA damage and repair as well as redox homeostasis and oxidative stress are key processes in cellular response to BaP suggesting a similar mode of action of BaP in yeast and mammals. Interestingly, toxicant export is also implicated as a potential novel modulator of cellular susceptibility. In particular, we identified several transporters with human orthologs (solute carrier family 22) which may play a role in mammalian systems.
authors: Vulpe Laboratory, Graduate Group in Environmental Health Sciences, University of California Berkeley, CA, USA.
authors: Sean Timothy Francis
authors: ST
authors: O'Connor
authors: Jiaqi
authors: J
authors: Lan
authors: Matthew
authors: M
authors: North
authors: Alexandre
authors: A
authors: Loguinov
authors: Luoping
authors: L
authors: Zhang
authors: Martyn T
authors: MT
authors: Smith
authors: April Z
authors: AZ
authors: Gu
authors: Chris
authors: C
authors: Vulpe
keywords: S-9; benzo[a]pyrene; ontology; resistance; sensitivity; stress; toxicity; yeast
references: Toxicol Appl Pharmacol. 1997 May;144(1):62-9
references: 9169070
references: Cancer Lett. 1997 Feb 26;113(1-2):205-12
references: 9065823
references: Biochim Biophys Acta. 1978 Dec 18;544(3):615-23
references: 215227
references: Environ Mol Mutagen. 2005 Mar-Apr;45(2-3):106-14
references: 15688365
references: Environ Health Perspect. 2001 Jan;109(1):71-4
references: 11171528
references: J Appl Toxicol. 2008 May;28(4):491-508
references: 17879257
references: Cancer Res. 2006 Mar 1;66(5):2616-20
references: 16510580
references: Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1371-5
references: 8108418
references: Chem Biol Interact. 2010 Mar 19;184(1-2):86-93
references: 20026094
references: Cancer Res. 1978 Feb;38(2):354-8
references: 620406
references: Fundam Appl Toxicol. 1990 Oct;15(3):510-6
references: 2258015
references: Toxicol Appl Pharmacol. 2009 Dec 15;241(3):294-302
references: 19732783
references: Biochemistry. 2003 Sep 30;42(38):11253-62
references: 14503875
references: Biochem Biophys Res Commun. 1974 Sep 9;60(1):460-7
references: 4609128
references: Nature. 2003 Oct 16;425(6959):686-91
references: 14562095
references: Mutat Res. 2008 Nov 17;657(1):3-7
references: 18801460
references: Chemosphere. 2002 Sep;48(8):843-8
references: 12222778
references: Nature. 1987 Sep 10-16;329(6135):131-4
references: 3306404
references: Carcinogenesis. 2006 Mar;27(3):646-55
references: 16269432
references: Sci Total Environ. 2004 Jun 29;326(1-3):143-9
references: 15142772
references: Genome Biol. 2004;5(3):R18
references: 15003121
references: Toxicol Sci. 2009 Oct;111(2):202-25
references: 19567883
references: Annu Rev Physiol. 2005;67:225-57
references: 15709958
references: Microbiol Rev. 1986 Sep;50(3):244-58
references: 3534536
references: Nat Protoc. 2007;2(11):2958-74
references: 18007632
references: Toxicol Sci. 2009 Oct;111(2):424-36
references: 19635755
references: DNA Repair (Amst). 2009 Jan 1;8(1):40-50
references: 18817898
references: Oncogene. 2004 Aug 23;23(38):6500-23
references: 15322521
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Nature. 2002 Sep 12;419(6903):135-41
references: 12226657
references: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W330-4
references: 16845020
references: PLoS One. 2011;6(8):e24205
references: 21912624
references: Toxicol Sci. 2012 Sep;129(1):157-65
references: 22641617
references: Biochem Biophys Res Commun. 1978 May 15;82(1):33-8
references: 27189
references: Cancer Res. 2007 Feb 15;67(4):1696-705
references: 17308111
references: Toxicol Appl Pharmacol. 2007 Jun 1;221(2):203-14
references: 17466351
references: Nucleic Acids Res. 2011 Jul;39(13):e87
references: 21543451
references: Mol Cell. 2001 Nov;8(5):1105-15
references: 11741545
references: Toxicol Ind Health. 1991 May;7(3):141-57
references: 1949056
references: OMICS. 2009 Apr;13(2):115-25
references: 19245359
references: PLoS Genet. 2012;8(3):e1002573
references: 22438825
references: Nature. 2002 Jul 25;418(6896):387-91
references: 12140549
references: BMC Bioinformatics. 2002 Nov 13;3:35
references: 12431279
references: Sci Total Environ. 1992 May 1;116(1-2):109-35
references: 1411492
references: RNA. 2008 Oct;14(10):2183-94
references: 18755837
references: J Toxicol Environ Health A. 2007 Nov;70(21):1858-65
references: 17934958
references: Biochem Res Int. 2012;2012:493894
references: 22550588
references: Drug Metab Rev. 2001 Feb;33(1):1-35
references: 11270659
references: Mutat Res. 1980 Jan;77(1):55-63
references: 6767185
references: Trends Microbiol. 2007 Feb;15(2):78-86
references: 17187982
references: Am J Physiol Heart Circ Physiol. 2001 Mar;280(3):H1293-300
references: 11179076
references: J Pharmacol Toxicol Methods. 2001 Nov-Dec;46(3):169-72
references: 12183193
references: Toxicol Sci. 2011 Sep;123(1):123-32
references: 21715664
references: Mol Gen Genet. 1983;192(3):466-70
references: 6361490
references: Food Chem Toxicol. 2011 Jun;49(6):1340-5
references: 21419819
references: Pharm Res. 2006 Nov;23(11):2586-94
references: 17048120
references: Cancer Res. 1983 Feb;43(2):485-90
references: 6293698
references: Environ Health Perspect. 2011 Jun;119(6):771-7
references: 21193388
references: Toxicol Sci. 2002 Dec;70(2):193-201
references: 12441364
references: Toxicol Lett. 1982 Apr;11(1-2):35-42
references: 6283696
references: Mutat Res. 1988 Oct;206(2):209-16
references: 3050501
references: Cancer Res. 1980 Nov;40(11):4070-5
references: 6258771
references: Anal Biochem. 1982 May 1;122(1):129-38
references: 7048997
references: DNA Repair (Amst). 2005 Nov 21;4(11):1281-94
references: 16043424
references: Nucleic Acids Res. 2002 Jan 1;30(1):31-4
references: 11752246