Pathways Controlling Genome Stability and Mutation

描述(由申请人提供)：RAD6介导的复制后修复和突变途径对酵母和哺乳动物细胞的基因组稳定性都是至关重要的。RAD6途径由几个子分支组成，这些子分支与其他修复途径连接，在无错误和突变结果之间划分损伤。没有这条途径，细胞是不变的。尽管突变对人类健康具有明显的重要性，但目前我们对这一途径的了解有限。我们正在开发系统的方法来识别这一途径的基因，最近报道了几个新的无错亚分支基因。然而，为了了解突变，关键是要了解无错误和致突变的亚分支，以及损伤是如何在它们和其他途径之间分配的。因此，我们建议对三个已经确定的基因进行进一步的鉴定，这些基因要么在无错误反应中起作用，要么在重组或细胞周期的界面上发挥作用。我们还建议将该方法扩展到识别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在无错误响应中所扮演的角色。 2)利用全基因组筛选产生一组候选突变基因。 3)确定真实的诱变基因，并确定最关键的突变。 4)确定诱变基因在诱变反应中的作用。 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.