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Understanding the mechanisms of MMS21 in genome instability through mutations in Saccaramyces cerevisiae and human

Investigator: Yee Mon Thu, PhD, Colby College

yee mon thé

Genome instability describes a condition in which the accuracy of genetic information or structural integrity of the genome is compromised. Under such a condition, the DNA molecule may be chemically altered with abreak in the double-strand or a bulky adduct that impedes normal progression of DNA replication. To restore genome integrity, concerted actions among proteins in DNA repair and response processes is crucial. Theseproteins are able to receive a multitude of signals yet their response must be specific to a particular type of DNA lesion so that it can be resolved in a timely manner. In this study, we propose to investigate how Mms21,a protein in DNA repair and response, with diverse roles is able to contribute to specific repair pathways. Defects in Mms21’s function or deviation from its normal expression have been reported in genetic diseasessuch as cancer. Notably, truncation of the C-terminus of the protein is observed in a genetic conditioncharacterized by dwarfism, genome instability, and insulin resistance. Molecular consequences of the mutation remain unclear. Leveraging the functional conservation between budding yeast and human, we propose to create multiple mutants in budding yeast. We will characterize their phenotypes to illustrate the molecular consequences of the human mutation and to test the hypothesis that the C-terminus of Mms21can influence the protein’s ability to respond to specific types of DNA damage. We will use functional genomic approaches such as chemical-genetic profiling and genetic interactions in a targeted manner toaddress the research questions. The approaches used in this project demonstrate how clinical data can be utilized to address basic science questions. Experiencing these approaches is valuable for young scientists to appreciate the complementary nature of applied and basic sciences.