Molecular mechanisms of genome maintenance during DNA replication and repair

项目摘要 DNA复制是一个基本的过程，包括基因组的准确复制以及 染色质修饰和表观遗传学信息的重建。DNA损伤干扰 复制保真度，导致突变和染色体易位的积累，从而导致 基因组不稳定。DNA损伤响应(DDR)的功能是通过招募 修复蛋白质，激活检查点，促进细胞凋亡。癌症以基因组为特征 不稳定，更需要有功能的复员方案途径。这为治疗提供了机会 干预，近年来，针对DDR的成分开发了抑制剂。这个 这项建议的总体目标是阐明在DNA过程中操作的基因组维持机制 复制。为了解决这一广泛的目标，我提出了三个目标：1)确定 单链DNA结合蛋白(RPA)调节DDR蛋白SMARCAL1的发现和功能 一种新的可替代单链DNA结合蛋白的鉴定及3)机制的理解 DNA修复蛋白如何在染色质结构中发挥作用。而目标1和目标2将于#年完成 我的博士后学习结束了，目标3代表了我在博士后研究的方向 工作。为了实现这些目标，我将利用新的方法，如单分子，全基因组和 蛋白质组学方法以及生化、分子和遗传技术。完成拟议的 AIMS将对新的基因组维护途径产生重要的见解，并将加深我们对 癌症生物发生的机制。

Project Summary DNA replication is a fundamental process that includes the accurate duplication of the genome as well as the re-establishment of chromatin modifications and epigenetic information. DNA damage interferes with replication fidelity, leading to an accumulation of mutations and chromosomal translocations, which cause genome instability. The DNA damage response (DDR) functions to resolve replication problems by recruiting repair proteins, activating checkpoints and promoting apoptosis. Cancers are characterized by genome instability and have a greater need for functional DDR pathways. This provides opportunities for therapeutic intervention, and in recent years, inhibitors have been developed targeting components of the DDR. The overall goal of this proposal is to elucidate the mechanisms of genome maintenance that operate during DNA replication. To address this broad goal, I propose three aims – 1) To determine the mechanisms by which the single strand DNA binding protein, RPA, regulates the DDR protein, SMARCAL1 2) Discovery and functional characterization of a novel alternative single strand DNA binding protein and 3) Mechanistic understanding of how DNA repair proteins work in the context of chromatin structure. While aims 1 and 2 will be completed by the end of my pre-doctoral studies, aim 3 represents the research direction I will adopt in my post-doctoral work. To accomplish these aims, I will utilize new methods such as single molecule, genome wide and proteomic approaches, as well as biochemical, molecular and genetic techniques. Completion of the proposed aims will yield significant insights into novel genome maintenance pathways and will further our understanding of the mechanisms underlying cancer biogenesis.