Choreography of Eukaryotic DNA Replication

项目摘要 DNA复制对生命至关重要，因此，细胞已经进化出机制， 监测复制保真度并协调复制的完成与其他细胞周期事件。的 这个项目的目标是了解细胞如何编排染色体的复制，以及如何 DNA复制的缺陷可能导致人类的某些疾病。染色体复制 真核生物是一个涉及每条染色体多个起始位点（起源）调节的过程 它们的起始时间（不是所有的起源都在S阶段同时发射）和效率（不是所有的 在每个细胞周期中的起源火）。因此，了解如何监管原产地使用至关重要， 了解基因组完整性是如何维持的。遗传性疾病强调了这一概念， 复制缺陷的链接：1）Meier-Gorlin综合征，其起源必需基因的点突变 许可; 2）小鼠chaos 3突变的基因编码部分的复制解旋酶，这是相关的 与小鼠乳腺癌的关系;以及3）可能导致人类乳腺癌的复制叉错误形式 片段拷贝数变异和自身免疫性疾病如红斑狼疮。酵母是理想的 研究DNA复制的模式生物，因为它的染色体小，起源明确 序列，易于改变染色体结构，以及遗传和基因组学的特殊系统 分析.这个项目将解决悬而未决的问题，为什么染色体的编排 复制在真核生物中如此重要：为什么起点在不同的时间启动复制， 区分不同时间类别的起源，低效起源的分子基础是什么， 复制起点发射和/或叉进展中的缺陷如何导致基因组不稳定性， 后续疾病状态？

PROJECT SUMMARY DNA replication is undeniably important for life and as a consequence, cells have evolved mechanisms to monitor replication fidelity and to coordinate completion of replication with other cell cycle events. The goal of this project is to understand how cells choreograph the duplication of their chromosomes, and how defects in DNA replication may contribute to some disorders in humans. Chromosome replication in eukaryotes is a process that involves the regulation of multiple initiation sites (origins) per chromosome that vary in their initiation timing (not all origins fire at the same time in S phase) and efficiency (not all origins fire in every cell cycle). Understanding how origin use is regulated is therefore critical for understanding how genome integrity is maintained. This notion is underscored by genetic disorders with links to replication defects: 1) Meier-Gorlin Syndrome with its point mutations in genes essential for origin licensing; 2) the mouse chaos3 mutation in a gene encoding part of the replicative helicase that is associated with breast cancer in mice; and 3) forms of replication fork errors that potentially contribute to human segmental copy number variants and autoimmune disorders such as lupus erythematosus. Yeast is an ideal model organism for studying DNA replication because of its small chromosomes, well defined origin sequences, ease of altering chromosome structure, and exceptional systems for genetic and genomic analysis. This project will address outstanding questions regarding why the choreography of chromosome replication is so important in eukaryotes: why do origins initiate replication at different times, what distinguishes origins in different temporal categories, what is the molecular basis for inefficient origins, and how do defects in replication origin firing and/or fork progression lead to genome instability and consequent disease states?