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信息的重建。DNA损伤会干扰 复制保真度，导致突变和染色体易位的积累， 基因组不稳定性DNA损伤反应（DDR）的功能是通过招募来解决复制问题 修复蛋白，激活检查点和促进细胞凋亡。癌症的特征是基因组 不稳定，更需要功能性DDR途径。这为治疗提供了机会。 近年来，已经开发了靶向DDR组分的抑制剂。的 该提案的总体目标是阐明在DNA合成过程中基因组维持的机制。 复制的为了实现这一广泛目标，我提出了三个目标：1）确定 单链DNA结合蛋白RPA调节DDR蛋白SMARCAL 1 2）发现和功能 一种新的替代单链DNA结合蛋白的表征和3）对 DNA修复蛋白如何在染色质结构的背景下工作。虽然目标1和2将于 在我的博士前学习结束之际，目标3代表了我在博士后阶段的研究方向 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， 蛋白质组学方法以及生物化学、分子和遗传技术。完成建议 aims将对新的基因组维持途径产生重要的见解，并将进一步加深我们的理解 癌症生物发生的潜在机制

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.