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Inhibition of an E. coli DNA glycosylase, MutM, by non-native metals

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dc.contributorWoski, Stephen A.
dc.contributorPan, Shanlin
dc.contributorCassady, Carolyn J.
dc.contributorMarcus, Stevan
dc.contributor.advisorBusenlehner, Laura S.
dc.contributor.authorAn, Mier
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.date.accessioned2017-03-01T16:46:37Z
dc.date.available2017-03-01T16:46:37Z
dc.date.issued2013
dc.descriptionElectronic Thesis or Dissertationen_US
dc.description.abstractNon-native metals are well recognized carcinogens; however, most exhibit low mutagenicity. One route by which metals could contribute to carcinogenesis is by inhibition of crucial DNA repair processes. The protein targets and mechanism of inhibition, however, are not fully understood. DNA repair proteins that contain zinc finger motifs are potential targets because of their high affinity for metal ions. Insight into the ability of non-native metals to displace the native metal, zinc, and the mechanism they use to inhibit protein function is needed to fully understand this pathway¡¦s contribution to metal-induced cancer. In this dissertation, we probe MutM, an Escherichia coli zinc finger–——containing DNA glycosylase/AP lyase that excises oxidized guanine bases, 8-oxoguanine, from double stranded DNA. We identify that Zn(II)–——, Cd(II)–—— and Co(II)–——MutM complexes coordinate metal ions in the zinc finger motif in a 1:1 stoichiometric ratio. We demonstrate, for the first time, that Cd(II)binding to the MutM zinc finger affects the recognition of 8-oxoguanine containing DNA and inhibits the glycosylase activity, the first step in the mechanism. However, Co(II)–——MutM retains most of the native enzymatic activity, demonstrating the specificity for certain non-native metals. Furthermore, we characterize the conformational and dynamic changes of MutM caused by Cd(II) binding that contribute to the loss of glycosylase activity. This is the first study to relate non-native metal induced changes in structure of zinc finger DNA repair proteins to the mechanism of metal inhibition.en_US
dc.format.extent121 p.
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.otheru0015_0000001_0001161
dc.identifier.otherAn_alatus_0004D_11374
dc.identifier.urihttps://ir.ua.edu/handle/123456789/1638
dc.languageEnglish
dc.language.isoen_US
dc.publisherUniversity of Alabama Libraries
dc.relation.hasversionborn digital
dc.relation.ispartofThe University of Alabama Electronic Theses and Dissertations
dc.relation.ispartofThe University of Alabama Libraries Digital Collections
dc.rightsAll rights reserved by the author unless otherwise indicated.en_US
dc.subjectBiochemistry
dc.titleInhibition of an E. coli DNA glycosylase, MutM, by non-native metalsen_US
dc.typethesis
dc.typetext
etdms.degree.departmentUniversity of Alabama. Department of Chemistry
etdms.degree.disciplineChemistry
etdms.degree.grantorThe University of Alabama
etdms.degree.leveldoctoral
etdms.degree.namePh.D.

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