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dc.contributor.authorEdwards, Yasmin
dc.date.accessioned2018-07-12T17:37:38Z
dc.date.available2018-07-12T17:37:38Z
dc.date.issued2011
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 72-11, Section: B, page: 6527.;Advisors: Winfried Edelmann.
dc.identifier.urihttps://yulib002.mc.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3467978
dc.identifier.urihttps://hdl.handle.net/20.500.12202/1241
dc.description.abstractHereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome, caused by mutations in several of the DNA mismatch repair (MMR) genes. MutS homologue 3 (MSH3) is a member of the MMR protein family. The protein is involved in repair of 1--4 base pair insertion/deletion mutations. These mutations occur due to slippage of DNA polymerase at repeat sequences. No mutations in the MSH3 gene have been associated with HNPCC families. An Msh3 knock-out mouse model displays a late onset tumor phenotype. To further elucidate the functions of the MSH3 protein in tumor suppression, a knock-in mouse model was generated carrying an Msh3G855D mutation in the Walker A motif of the ATPase domain. This mutation resulted in loss of the ATPase function of the protein. The MSH3 protein is known to be involved in triplet repeat expansion diseases, recombination repair in yeast, and has a novel role in repair of some single base pair mismatches. In addition, recent epidemiological studies found that MSH3 gene variants are associated with increased risk for several types of sporadic cancers. We found that the Msh3 protein has a novel function in DNA double strand break repair and maintaining chromosomal stability. The animals demonstrated increased microsatellite instability, reduced survival and an increase in tumorigenesis. This analysis shows that a mutation in the Msh3 ATPase domain can reduce the genome maintenance and tumor suppressor function of the protein. This has important implications relating to known disease processes with which the protein has been associated.
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.subjectGenetics.
dc.subjectOncology.
dc.titleMsh3 knock-in mouse model demonstrates novel functions of the protein in genome maintenance
dc.typeDissertation


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