title: The uracil DNA glycosylase UdgB of Mycobacterium smegmatis protects the organism from the mutagenic effects of cytosine and adenine deamination.
abstract: Spontaneous hydrolytic deamination of DNA bases represents a considerable mutagenic threat to all organisms, particularly those living in extreme habitats. Cytosine is readily deaminated to uracil, which base pairs with adenine during replication, and most organisms encode at least one uracil DNA glycosylase (UDG) that removes this aberrant base from DNA with high efficiency. Adenine deaminates to hypoxanthine approximately 10-fold less efficiently, and its removal from DNA in vivo has to date been reported to be mediated solely by alkyladenine DNA glycosylase. We previously showed that UdgB from Pyrobaculum aerophilum, a hyperthermophilic crenarchaeon, can excise hypoxanthine from oligonucleotide substrates, but as this organism is not amenable to genetic manipulation, we were unable to ascertain that the enzyme also has this role in vivo. In the present study, we show that UdgB from Mycobacterium smegmatis protects this organism against mutagenesis associated with deamination of both cytosine and adenine. Together with Ung-type uracil glycosylase, M. smegmatis UdgB also helps attenuate the cytotoxicity of the antimicrobial agent 5-fluorouracil.
authors.affiliation: Institute of Medical Microbiology, University of Zurich, and National Centre for Mycobacteria, Gloriastrasse 30, CH-8006 Zurich,Switzerland.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Wanner
authors.forename: Dennis
authors.initials: D
authors.lastname: Castor
authors.forename: Carolin
authors.initials: C
authors.lastname: Güthlein
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.forename: Burkhard
authors.initials: B
authors.lastname: Springer
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
mesh_terms: D000192:Actinomycetales / Q000201:enzymology / Q000235:genetics; D000225:Adenine; D000595:Amino Acid Sequence; D016923:Cell Death; D003596:Cytosine / Q000378:metabolism*; D003641:Deamination; D017353:Gene Deletion; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020102:Mycobacterium smegmatis / Q000201:enzymology*; D041543:Pyrobaculum / Q000201:enzymology / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D003596:Cytosine; D013940:Thymidylate Synthase; D051981:Uracil-DNA Glycosidase; D000225:Adenine
references.citation: Mol Microbiol. 1995 Jun;16(5):991-1000
references.pmid: 7476195
references.citation: J Biol Chem. 1993 Oct 5;268(28):21218-24
references.pmid: 8407958
references.citation: Nucleic Acids Res. 1990 Sep 11;18(17):5069-75
references.pmid: 1698278
references.citation: Mutat Res. 2000 Aug 30;460(3-4):165-81
references.pmid: 10946227
references.citation: J Bacteriol. 1982 Jul;151(1):351-7
references.pmid: 6282808
references.citation: Clin Microbiol Rev. 2006 Jul;19(3):558-70
references.pmid: 16847086
references.citation: Mol Cell Biol. 2003 Nov;23(22):8386-94
references.pmid: 14585995
references.citation: J Mol Biol. 2006 Jan 6;355(1):20-33
references.pmid: 16297932
references.citation: Nature. 1980 Oct 9;287(5782):560-1
references.pmid: 6999365
references.citation: Biochemistry. 1986 Jun 3;25(11):3225-30
references.pmid: 3524674
references.citation: J Bacteriol. 1988 Mar;170(3):1069-75
references.pmid: 2830228
references.citation: EMBO J. 1999 Jul 1;18(13):3834-44
references.pmid: 10393198
references.citation: Mol Microbiol. 2004 Sep;53(6):1601-9
references.pmid: 15341642
references.citation: Prog Nucleic Acid Res Mol Biol. 1994;48:315-70
references.pmid: 7938553
references.citation: J Bacteriol. 1997 May;179(10):3298-303
references.pmid: 9150227
references.citation: Biochemistry. 1968 Jan;7(1):448-55
references.pmid: 5758560
references.citation: EMBO J. 2002 Jun 17;21(12):3182-91
references.pmid: 12065430
references.citation: Biochemistry. 1995 Jan 10;34(1):128-38
references.pmid: 7819187
references.citation: J Biol Chem. 2000 Jun 23;275(25):19146-9
references.pmid: 10777501
references.citation: Chembiochem. 2003 Oct 6;4(10):1078-88
references.pmid: 14523926
references.citation: Nucleic Acids Res. 2002 May 15;30(10):2097-102
references.pmid: 12000829
references.citation: Mol Microbiol. 2008 Apr;68(1):202-15
references.pmid: 18312272
references.citation: DNA Repair (Amst). 2005 Dec 8;4(12):1421-31
references.pmid: 16216562
references.citation: Mutat Res. 1992 Aug;277(2):139-62
references.pmid: 1378531
references.citation: J Biol Chem. 2002 May 10;277(19):16936-40
references.pmid: 11877410
references.citation: J Biol Chem. 1977 May 25;252(10):3286-94
references.pmid: 324994
references.citation: Curr Biol. 1999 Feb 25;9(4):174-85
references.pmid: 10074426
references.citation: DNA Repair (Amst). 2007 Oct 1;6(10):1517-28
references.pmid: 17588829
references.citation: Curr Biol. 1999 May 20;9(10):531-4
references.pmid: 10339434
references.citation: Mol Pharmacol. 2004 Sep;66(3):620-6
references.pmid: 15322254
references.citation: J Bacteriol. 2009 Jan;191(2):555-62
references.pmid: 19011038
references.citation: Mol Microbiol. 1990 Nov;4(11):1911-9
references.pmid: 2082148
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W332-5
references.pmid: 15215405
references.citation: Biochemistry. 1974 Jul 30;13(16):3405-10
references.pmid: 4601435
references.citation: J Mol Biol. 2003 Oct 24;333(3):515-26
references.pmid: 14556741
references.citation: J Bacteriol. 1981 Feb;145(2):687-95
references.pmid: 6109711
references.citation: Curr Issues Mol Biol. 2006 Jul;8(2):97-111
references.pmid: 16878362
references.citation: Nucleic Acids Res. 1991 Aug 25;19(16):4473-8
references.pmid: 1886771
references.citation: Mol Pharmacol. 1982 Jan;21(1):211-6
references.pmid: 6215571
references.citation: Nature. 1993 Apr 22;362(6422):709-15
references.pmid: 8469282