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

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dc.contributor Woski, Stephen A.
dc.contributor Pan, Shanlin
dc.contributor Cassady, Carolyn J.
dc.contributor Marcus, Stevan
dc.contributor.advisor Busenlehner, Laura S. An, Mier
dc.contributor.other University of Alabama Tuscaloosa 2017-03-01T16:46:37Z 2017-03-01T16:46:37Z 2013
dc.identifier.other u0015_0000001_0001161
dc.identifier.other An_alatus_0004D_11374
dc.description Electronic Thesis or Dissertation en_US
dc.description.abstract Non-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.extent 121 p.
dc.format.medium electronic
dc.format.mimetype application/pdf
dc.language English
dc.language.iso en_US
dc.publisher University of Alabama Libraries
dc.relation.ispartof The University of Alabama Electronic Theses and Dissertations
dc.relation.ispartof The University of Alabama Libraries Digital Collections
dc.relation.hasversion born digital
dc.rights All rights reserved by the author unless otherwise indicated. en_US
dc.subject Biochemistry
dc.title Inhibition of an E. coli DNA glycosylase, MutM, by non-native metals en_US
dc.type thesis
dc.type text University of Alabama. Department of Chemistry Chemistry The University of Alabama doctoral Ph.D.

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