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于酵母和哺乳动物细胞中的基因组稳定性至关重要。RAD6通路由几个子分支组成，这些子分支与其他修复通路相互作用，以在无错误和致突变结果之间划分损伤。没有这个途径，细胞是不可变的。尽管突变对人类健康的重要性显而易见，但我们目前对这一途径的理解有限。我们正在开发系统的方法来确定这一途径的基因，并在最近报道了几个新的基因的错误的子分支。然而，为了理解突变，关键是要理解无错误和致突变的子分支，以及如何在它们和其他途径之间分配损害。因此，我们提出了进一步表征三个，已经确定的基因，其功能在无错误的反应，或在接口与重组或细胞周期。我们还提出了该方法的扩展，以确定和表征诱变子分支的重要基因。拟议研究的具体目标如下： 1)描述DOA1、ESC4和WSS1在无错误响应中扮演的角色。 2)使用全基因组筛选产生一组候选诱变基因。 3)确定真正的诱变基因，并确定最关键的突变。 4)描述致突变基因在致突变反应中所起的作用。 这些研究有望帮助了解真核细胞何时以及如何突变，并将有助于我们理解对人类健康具有根本意义的问题，如衰老和癌症。

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.