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dc.contributor.advisorJohn M. Essigmann.en_US
dc.contributor.authorZdraveski, Zoran Z. (Zoran Zare), 1969-en_US
dc.contributor.otherMassachusetts Institute of Technology. Dept. of Chemistry.en_US
dc.date.accessioned2008-02-28T16:00:23Z
dc.date.available2008-02-28T16:00:23Z
dc.date.copyright2001en_US
dc.date.issued2002en_US
dc.identifier.urihttp://dspace.mit.edu/handle/1721.1/8363en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/8363
dc.descriptionThesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, February 2002.en_US
dc.descriptionVita.en_US
dc.descriptionIncludes bibliographical references (p. 129-158).en_US
dc.description.abstractCisplatin (cis-diamminedichloroplatinum(ll)) is a successful DNA-damaging anticancer drug used in the treatment of testicular, ovarian and other tumors. In the past decade, several mutually non-exclusive hypotheses have been presented to explain the cytotoxic and organotropic effects of this compound. In this work we have focused on the opposing effects of mismatch repair and recombination in mediating cisplatin cytotoxicity. Recombination mutants showed strikingly high sensitivity to cisplatin, while mismatch repair mutants showed low sensitivity and resistance to the drug. These results further illustrated that while recombination promotes cellular survival following cisplatin damage, mismatch repair, in contrast, promotes cisplatin toxicity. The mismatch repair protein MutS recognized cisplatin-DNA adducts with 2-fold higher affinity than adducts of oxaliplatin, a cisplatin analog that does not elicit resistance in mismatch repair mutants. MutS recognized the major cisplatin DNA-adduct, the 1,2-d(GpG) intrastrand crosslink, with equal affinity as a G/T mismatch in the same sequence context. Furthermore, MutS inhibited RecA catalyzed strand exchange reaction at the level of joint molecule formation when the substrate was platinated DNA. In the cell, mismatch repair could potentiate cisplatin toxicity by inhibiting the high levels of recombination that are required for cisplatin survival. Microarray analysis of gene expression following cisplatin damage showed that in contrast to wild type and methylation dam mutant, the methylation-mismatch repair double mutant did not show induction of any significant SOS DNA damage response.en_US
dc.description.abstract(cont.) Yet, this strain showed abrogated sensitivity in comparison to the dam mutant and high survival rate. The low damage response in the dam mutS mutants might allow for adduct tolerance and survival. Finally, genetic studies with yeast deficient in the meiosis specific mismatch repair proteins MSH4 and MSH5 showed both mutants to be resistant to cisplatin indicating that these proteins are involved in potentiating cisplatin toxicity. Taken together, these results further elucidate the role of recombination and mismatch repair in modulation of the cellular responses to cisplatin. Furthermore, because of the specific roles of these DNA metabolic pathways in meiotic cells, these results provide the framework in which the organotropic effects of cisplatin can be viewed from a molecular perspective.en_US
dc.description.statementofresponsibilityby Zoran Z. Zdraveski.en_US
dc.format.extent294 p.en_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/8363en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582
dc.subjectChemistry.en_US
dc.titleThe role of mismatch repair and recombination in cellular responses to the DNA damaging anticancer drug Cisplatinen_US
dc.typeThesisen_US
dc.description.degreePh.D.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistry
dc.identifier.oclc50549338en_US


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