Hoffert KM, Higginbotham KSP, Gibson JT, Oehrle S, Strome ED

Maintenance of genome integrity is a crucial cellular focus that involves a wide variety of proteins functioning in multiple processes. Defects in many different pathways can result in genome instability, a hallmark of cancer. Utilizing a diploid Saccharomyces cerevisiae model, we previously reported a collection of gene mutations that impact ...

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genome stability in a haploinsufficient state. In this work we explore the impact of gene dosage on genome instability for one of these genes and its paralog; SAM1 and SAM2 These genes encode S-AdenosylMethionine (AdoMet) synthetases, responsible for the creation of AdoMet from methionine and ATP. AdoMet is the universal methyl donor for methylation reactions and is essential for cell viability. It is the second most used cellular enzyme substrate and is exceptionally well conserved through evolution. Mammalian cells express three genes - MAT1A, MAT2A, and MAT2B - with distinct expression profiles and functions. Alterations to these AdoMet synthetase genes, and AdoMet levels, are found in many cancers, making them a popular target for therapeutic intervention. However significant variance in these alterations are found in different tumor types, with the cellular consequences of the variation still unknown. By studying this pathway in the yeast system, we demonstrate that losses of SAM1 and SAM2 have different impacts on genome stability through distinctive impacts on gene expression and AdoMet levels and ultimately separate impacts to the methyl cycle. Thus, this study provides insight into the mechanisms by which differential expression of the SAM genes have cellular consequences that impact genome instability.

Date: Jul. 18, 2019

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