Choreography of Eukaryotic DNA Replication

真核 DNA 复制的编排

• 批准号: 9900022
• 负责人: BONITA J BREWER
• 金额: $ 55.17万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900022
• 关键词: Address; Animal Model; Autoimmune Diseases; Basal Cell Nevus Syndrome; Biological Models; Categories; Cell Cycle; Cells; Chromosome Structures; Chromosome abnormality; Chromosomes; Copy Number Polymorphism; DNA biosynthesis; DNA replication fork; Defect; Disease; Eukaryota; Fire - disasters; Genes; Genetic; Genetic Diseases; Genomic Instability; Genomics; Goals; Human; Lead; Licensing; Life; Link; Lupus Erythematosus; Malignant Neoplasms; Molecular; Monitor; Mus; Mutation; Point Mutation; Process; Regulation; Replication Origin; S Phase; Site; System; Time; Work; Yeasts; chromosome replication; developmental disease; event cycle; genome integrity; helicase; malignant breast neoplasm

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?

项目总结 DNA复制对生命的重要性毋庸置疑，因此，细胞进化出了 监测复制的保真度，并将复制的完成与其他细胞周期事件协调。这个 这个项目的目标是了解细胞如何编排其染色体的复制，以及如何 DNA复制缺陷可能会导致人类的某些疾病。染色体复制在 真核生物是一个涉及每条染色体多个起始点(起始点)调控的过程。 它们在启动时间(不是所有的起源在S阶段都同时点火)和效率(并不是所有的起源)上都不同 起源于每个细胞周期中的火)。因此，了解原产地使用是如何受到监管的至关重要 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 与复制缺陷有关：1)Meier-Gorlin综合征及其起源所必需的基因点突变 许可；2)小鼠编码部分复制解旋酶的基因Chaos3突变 与小鼠的乳腺癌有关；以及3)可能对人类有贡献的复制分叉错误 片段拷贝数变异和自身免疫性疾病，如红斑狼疮。酵母是一种理想的选择 研究DNA复制的模式生物，因为它的染色体很小，来源明确 序列，易于改变染色体结构，以及用于遗传和基因组的特殊系统 分析。这个项目将解决悬而未决的问题，即为什么染色体的编排 复制在真核生物中是如此重要：为什么起源在不同的时间启动复制， 区分不同时间类别的起源，无效起源的分子基础是什么，以及 复制起点激发和/或分叉进程中的缺陷如何导致基因组不稳定和 由此产生的疾病状态？