Choreography of Eukaryotic DNA Replication

项目摘要 基因组的忠实复制是所有分裂细胞的核心使命。因此，细胞已经进化 监测复制保真度并与其他细胞周期协调复制完成的机制 事件在真核生物中，染色体复制起始于多个起始位点（起点），这是一个复杂的过程。 细胞调节机制的关键目标，确保适当的基因组维护。细胞可以调节 来源选择（他们使用哪些潜在的来源），效率（他们在任何给定的细胞中使用它的可能性如何 周期）和起始时间，以编排基因组的整体复制。破坏这种 舞蹈编排与包括癌症在内的多种人类疾病有关。虽然起源不是 在序列水平上保守，蛋白质机制是高度保守的，允许发现关键 这些基本过程的方面在简单的模型，如面包酵母，因为它的小 染色体，明确定义的起源序列，易于改变染色体结构， 基因和基因组分析系统。最近的一项发现是rDNA-the 一个含有核糖体RNA基因串联重复拷贝的基因座--调节基因组复制 和维护在接下来的五年里，这个项目将调查如何编排的 染色体复制的建立以及为什么它在真核生物中如此重要：rDNA如何复制 rDNA拷贝数是如何影响基因组稳定性的？原产地偏好和 复制时间决定全基因组？基因组编排的改变 复制有助于表型，如那些在人类疾病？

PROJECT SUMMARY Faithful replication of the genome is a core mission of all dividing cells. Accordingly, cells have evolved mechanisms to monitor replication fidelity and to coordinate completion of replication with other cell cycle events. In eukaryotes, chromosome replication is initiated at multiple initiation sites (origins), which are a key target of the cell’s regulatory mechanisms ensuring proper genome maintenance. Cells can regulate origin choice (which potential origins they use), efficiency (how likely they are to use it in any given cell cycle), and initiation time, to choreograph the overall duplication of the genome. Disruption of this choreography has been linked to a variety of human disorders including cancer. Although origins are not conserved at the sequence level, the protein machinery is highly conserved, allowing discovery of key aspects of these fundamental processes in simple models such as Baker’s yeast because of its small chromosomes, well defined origin sequences, ease of altering chromosome structure, and exceptional systems for genetic and genomic analysis. A recent discovery is the key role played by the rDNA—the locus containing tandemly-repeated copies of ribosomal RNA genes—in modulating genome duplication and maintenance. Over the next five years, this project will investigate how the choreography of chromosome replication is established and why it is so important in eukaryotes: How is rDNA replication regulated, and how does rDNA copy number affect genome stability? How are origin preference and replication timing determined genome-wide? And how do alterations in the choreography of genome replication contribute to phenotypes such as those seen in human disorders?