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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    Analysis of DNA mismatch repair genetic interactions in yeast and mouse

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    Date
    2013
    Author
    Tosti, Elena
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    Abstract
    The DNA mismatch repair (MMR) system is responsible for correcting base substitution and insertion-deletion mutations (IDLs) generated during erroneous replication in bacteria, yeast and mammals. MMR complexes also recognize damaged-base mispairs resulting from environmental exposure to DNA damaging agents. The loss of MMR causes a 'mutator' phenotype, resulting in the genome-wide accumulation of mutations, and is the underlying cause for Hereditary Nonpolyposis Colorectal Cancer / Lynch Syndrome (HNPCC/LS) and a significant proportion of sporadic colorectal cancer. The presence of alterations in length of 1-4 base nucleotide repeats (microsatellites), interspersed throughout the genome, is associated with MMR deficiency (microsatellite instability, MSI). Genes presenting "microsatellite-like" repeats in their coding regions are commonly mutated in MSIpositive colon cancers. One of the most frequently mutated genes in HNPCC/LS is the Transforming Growth Factor-beta receptor type II gene (TGFbeta-RII). Therefore the first project of my thesis was focused on testing whether TGF-betaR11 inactivation promotes colon tumorigenesis in a MMR deficient mouse model. I developed the first colon tumor model in a MMR deficient background. Moreover, this model resembles inflammatory-associated colon cancers in the context of MMR deficiency; hence, it offers a more faithful system to investigate critical oncogenic steps underlying inflammation-associated colon tumorigenesis and further to test the efficiency of chemotherapeutics treatments. MMR-deficient tumors also display resistance to DNA damaging agents and, as a consequence, are resistant to a variety of commonly used chemotherapeutic agents. Thus, the development of novel therapeutic strategies, targeting MMRdeficient cancer cells more efficiently, would be highly desirable. A promising new direction to identify potential targets for anticancer treatment is the harnessing of synthetic lethality. Here, we have identified conserved synthetic lethal / sick genetic interactions (GIs) for MMR factors between two distant yeast species, Schizosaccharomyces pombe (S. pombe) and Saccharomyces cerevisiae (S. cerevisiae). Specifically, we have identified a conserved negative genetic relationship between Msh2, a major MMR component mutated in colorectal cancer, and Senp6 protease, which regulates the deSUMOylation of a range of genome maintenance proteins. Our findings suggest that Senp6 is a promising new target for the treatment of MMR-deficient cancers.
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    https://ezproxy.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:3569848
    https://hdl.handle.net/20.500.12202/1393
    Citation
    Source: Dissertation Abstracts International, Volume: 74-08(E), Section: B.;Advisors: Ulrich Steidl.
    *This is constructed from limited available data and may be imprecise.
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    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

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