Platinum coordination to RNA

dc.contributor.authorChapman, Erich G., 1984-
dc.date.accessioned2011-04-11T23:07:50Z
dc.date.available2011-04-11T23:07:50Z
dc.date.issued2010-12
dc.descriptionxix, 111 p. : ill. (some col.)en_US
dc.description.abstractSince discovery of its biological effects in the late 1960's, cisplatin (cis-diamminedichloroplatinum( II)) has become one of the most broadly-prescribed cancer drugs in use today. A majority of efforts to understand the metallobiochemistry of this drug have focused on describing the interactions of cisplatin-derived Pt(II) complexes with DNA. Drug binding to this "high value" cellular target is believed to trigger the apoptotic pathways that underlie cisplatin's cytotoxic effects. Although RNA is chemically similar to DNA and responsible for accurately transferring, regulating, and transforming the same genetic information that is stored within the DNA genome, surprisingly little is known about platinum(II) drug binding to RNA. Accordingly, the first three chapters of this dissertation describe efforts to address questions regarding cisplatin coordination to RNA on the molecular scale. Chapter I reviews fundamental aspects of how metal complexes interact with nucleic acids, highlighting the bioinorganic chemistry of platinum(II) antitumor drugs. This chapter also introduces the idea that drug binding to RNA may form an important part of how these complexes work in the cell. Chapter II describes cisplatin crosslinking between RNA nucleobases located on opposite sides of the internal loop of an RNA subdomain derived from the catalytic core of the spliceosome. Chapter III describes how platinum adducts disrupt the activity of RNA processing enzymes similar to those that are necessary for maturation, maintenance and recycling of the transcriptome. Chapter III also describes the reversal of RNA platination using thiourea. The chemistry of platinum(II) is also characterized by preferential coordination to sulfur ligands, or thiophilicity. Incorporating this property into RNA chemistry, Chapters IV and V describe the reaction of platinum(II) complexes with phosphorothioate-substituted RNAs. Chapter IV describes engineering platinum(II) crosslinks in the Hammerhead ribozyme through the targeting of a platinum(II) complex to a specific phosphorothioate substitution installed in the active site of this catalytic RNA. Chapter V outlines efforts to characterize the cleavage and isomerization reactions promoted by platinum(II) coordination to phosphorothioate-substituted RNAs. Finally, Chapter VI summarizes the insights gained throughout the course of our studies and provides an outlook on the future of platinum-RNA chemistry. This dissertation includes co-authored material and previously published results.en_US
dc.description.sponsorshipCommittee in charge: Michael M. Haley, Chair; Victoria J. DeRose, Advisor; David R. Tyler; Andrew J. Berglund; Eric A. Johnsonen_US
dc.identifier.urihttps://hdl.handle.net/1794/11072
dc.language.isoen_USen_US
dc.publisherUniversity of Oregonen_US
dc.relation.ispartofseriesUniversity of Oregon theses, Dept. of Chemistry, Ph. D., 2010;
dc.subjectAntitumoren_US
dc.subjectCisplatinen_US
dc.subjectHammerhead ribozymesen_US
dc.subjectPlatinumen_US
dc.subjectRNAen_US
dc.subjectBiochemistryen_US
dc.subjectInorganic chemistryen_US
dc.subjectChemistry, Inorganic
dc.titlePlatinum coordination to RNAen_US
dc.typeThesisen_US

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