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 affect genome stability in a haploinsufficient state. In this work we explore the effect 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 effects on genome stability through distinctive effects on gene expression and AdoMet levels, and ultimately separate effects on the methyl cycle. Thus, this study provides insight into the mechanisms by which differential expression of the SAM genes have cellular consequences that affect genome instability.

中文翻译：

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S-腺苷甲硫氨酸合成酶基因 SAM1 和 SAM2 的突变对酿酒酵母基因组稳定性有不同影响。

维持基因组完整性是细胞的一个关键焦点，涉及在多个过程中发挥作用的多种蛋白质。许多不同途径的缺陷可能导致基因组不稳定，这是癌症的一个标志。利用二倍体酿酒酵母模型，我们之前报道了一系列在单倍不足状态下影响基因组稳定性的基因突变。在这项工作中，我们探讨了基因剂量对这些基因之一及其旁系同源基因组不稳定性的影响；SAM1 和 SAM2。这些基因编码 S-腺苷甲硫氨酸 (AdoMet) 合成酶，负责从甲硫氨酸和 ATP 生成 AdoMet。AdoMet 是甲基化反应的通用甲基供体，对于细胞活力至关重要。它是第二大最常用的细胞酶底物，并且在进化过程中保存得非常完好。哺乳动物细胞表达三种基因：MAT1A、MAT2A 和 MAT2B，具有不同的表达谱和功能。在许多癌症中发现了这些 AdoMet 合成酶基因和 AdoMet 水平的改变，使其成为治疗干预的热门目标。然而，在不同的肿瘤类型中发现这些改变存在显着差异，而这些变化对细胞的影响仍未知。通过研究酵母系统中的这条通路，我们证明了 SAM1 和 SAM2 的丢失通过对基因表达和 AdoMet 水平的独特影响，以及最终对甲基循环的不同影响，对基因组稳定性产生不同的影响。因此，这项研究深入了解了 SAM 基因的差异表达对影响基因组不稳定性的细胞后果的机制。