Pathways Controlling Genome Stability and Mutation

描述（由申请人提供）：RAD6介导的复制后修复和诱变途径对酵母和哺乳动物细胞的基因组稳定性至关重要。RAD6通路由几个亚分支组成，这些亚分支与其他修复通路连接，将损伤划分为无错误和致突变结果。没有这个通路，细胞是不可改变的。尽管突变对人类健康的重要性显而易见，但我们对这一途径的理解目前有限。我们正在开发系统的方法来识别这一途径的基因，最近报道了几个无错误亚分支的新基因。然而，为了理解突变，关键是要了解无错误和致突变亚分支，以及它们和其他途径之间的损伤是如何划分的。因此，我们建议进一步表征三个已经确定的基因，它们在无错误反应中起作用，或者在与重组或细胞周期的界面上起作用。我们还建议扩展该方法来识别和表征致突变亚分支的重要基因。拟建研究的具体目的如下：

DESCRIPTION (provided by applicant): The RAD6 mediated post-replication and repair and mutagenesis pathway is critical for genome stability in both yeast and mammalian cells. The RAD6 pathway is composed of several subbranches that interface with other repair pathways to partition damage between error-free and mutagenic outcomes. Without this pathway cells are immutable. Despite the obvious importance of mutation to human health, our understanding of this pathway is currently limited. We are developing systematic approaches to identify genes of this pathway and have recently reported several new genes of the error-free subbranch. However, in order to understand mutation it is critical to understand both the error-free and mutagenic subbranches, as well as how damage is partitioned between them and other pathways. We therefore propose the further characterization of three, already identified genes, which function in the error-free response, or at the interface with recombination or the cell cycle. We also propose the extension of the approach to identify and characterize important genes of the mutagenic subbranch. The specific aims of the proposed research are as follows: 1) Characterize the roles played by DOA1, ESC4, and WSS1 in the error-free response. 2) Generate a set of candidate mutagenesis genes using genome wide screens. 3) Determine authentic mutagenesis genes and identify the most critical for mutation. 4) Characterize the roles played by the mutagenesis genes in the mutagenic response. These studies are expected to help understand when and how eukaryotic cells mutate, and will contribute to our understanding of issues that are of fundamental significance to human health, such as aging and cancer.