Monday, September 25, 2023
9/25/2023
Abstract Variance in age of onset, type of cancer developed, and outcome occur in populations of women who carry the same BRCA1 mutations. One explanation for these different cancer risks relates to the potential for other genetic loci, termed modifier genes, to influence cancer risk. Commonly used methodologies to discover modifier genes rely either on prior knowledge of gene function or are discovered through genome-wide association studies, which are capable of determining loci of interest but not specific genes. These methodologies have therefore resulted in limited discovery of secondary genetic loci impacting cancer incidence. Identification of modifier loci has the potential to save lives and the healthcare system money, aiding in development of diagnostic tests for preemptive treatment, as with BRCA1 testing, and identifying mechanistic cause as a starting point for therapeutic treatments. In past studies, we identified heterozygous mutations that altered genome stability rates using diploid strains of Saccharomyces cerevisiae lacking rad9 to model BRCA1 deficient cells. We observed altered genome instability in a strain missing one of the S-AdenosylMethionine (AdoMet) synthetase genes (SAM), indicating the human homolog could be a potential cancer susceptibility gene. Sam1, and its paralog Sam2, play roles in the methyl cycle catalyzing the biosynthesis of AdoMet. Despite Sam1 and Sam2 having high levels of homology and findings that both proteins localize to the cytoplasm, differences in abundance, regulation of expression, and post-translational modifications have been found which speak to the differential regulation and use of these proteins by the cell. In humans, three genes, MAT1A, MAT2A, and MAT2B, encode subunits of the homologous AdoMet synthetases. These genes, and their product AdoMet, have been implicated in multiple cancer types, but the mechanism of action is not well understood because both increases and decreases in expression are associated with cancers. Our group has conducted studies of SAM gene dosage and determined the impacts of changes in AdoMet synthetase genes on genome stability. SAM1 and SAM2 clearly operate by two distinct mechanisms to impart different impacts on genome stability. Additional experiments conducted in rad9-deficient backgrounds add additional information to our model of these different mechanisms. This proposal builds on our current findings towards a more complete mechanistic understanding of regulation of AdoMet and a detailed characterization of the impacts of mutations; including effects on the methyl cycle and different types of genome instability. Our overarching goal is to understand the differences in the roles of the SAM1 and SAM2 genes and how both increases and decreases in expression of the homologous genes in humans might lead to cancer. This proposal meets the stated objectives of the R15 AREA program by involving undergraduate students in hypothesis driven research and strengthening the research environment at NKU.
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