Replication Licensing and the Cell Cycle

复制许可和细胞周期

• 批准号: 9900791
• 负责人: Jeanette Gowen Cook
• 金额: $ 32.21万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900791
• 关键词: Abnormal Cell; Address; Alleles; Basal Cell Nevus Syndrome; Biological Assay; Biological Process; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Maintenance; Cell Proliferation; Cell division; Cells; Chromosomes; Complex; DNA; DNA biosynthesis; DNA replication origin; Data; Defect; Degenerative Disorder; Development; Dwarfism; Ensure; Eukaryotic Cell; Funding; Future; G1 Phase; GMNN gene; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Growth; Homeostasis; Human; Human Cell Line; Human Genome; Kinetics; Knowledge; Lead; Length; Licensing; Licensing Factor; Light; Malignant Neoplasms; Methods; Molecular; Mutagenesis; Mutation; Normal Cell; Nuclear; Pathway interactions; Patients; Population; Process; Proliferating; Proteins; Regulation; Replication Licensing; Role; S Phase; Series; Set protein; Site; Source; Transformed Cell Line; Variant; Work; cell type; design; helicase; inhibitor/antagonist; innovation; insight; mutant; patient subsets; protein protein interaction; rate of change; replication stress; stress tolerance; success; tool; tumorigenesis; ubiquitin-protein ligase

SUMMARY Precise duplication of the entire human genome requires that many thousands of chromosomal initiation sites, known as DNA replication origins, are utilized exactly once per cell cycle. Origin licensing is accomplished through the DNA loading of precursor helicase complexes, and they are loaded exclusively during the G1 phase of the cell cycle. Licensing too few origins results in incomplete replication, and licensing origins that have already been replicated results in re-replication. Both situations are sources of genome instability that can lead to developmental defects, degeneration, or mutagenesis. Our goal is to understand how the origin licensing process is achieved and how it is organized to ensure appropriate cell proliferation and genome stability. Here, we propose to interrogate licensing control during early differentiation, explore the molecular mechanism of an essential but mysterious licensing factor, and identify the mechanisms and pathways that regulate origin licensing during cell cycle exit. We have designed innovative new tools and assays to quantify and manipulate origin licensing in different human cell lines. We seek answers to questions such as the following: 1) How is licensing coordinated to ensure genome stability over the course of profound G1 changes that occur during differentiation? 2) How does the Cdt1 licensing factor function and how is it controlled? 3) How is licensing blocked during the establishment and maintenance of cell cycle quiescence? Success in answering these questions will shed light on an essential biological process that is fundamental to organismal development and homeostasis. Moreover, we will investigate DNA replication and cell cycle control in cellular settings that have not yet been explored in anticipation of revealing entirely new aspects of cell proliferation control.

总结 整个人类基因组的精确复制需要数千个染色体起始位点， 称为DNA复制起点，每个细胞周期只使用一次。原产地许可证已完成 通过前体解旋酶复合物的DNA加载，并且它们仅在G1期加载 细胞周期的阶段。授权的源太少会导致不完整的复制，而授权的源 已经被复制的结果是重新复制。这两种情况都是基因组不稳定性的来源， 导致发育缺陷、退化或突变。我们的目标是了解 许可过程的实现，以及如何组织，以确保适当的细胞增殖和基因组 稳定在这里，我们建议在早期分化过程中询问许可控制，探索分子生物学机制。 一个重要但神秘的许可因素的机制，并确定机制和途径， 在细胞周期退出期间规范原产地许可。我们设计了创新的新工具和检测方法， 并在不同的人类细胞系中操纵起源许可。我们寻求问题的答案，如 1）如何协调许可以确保基因组在深刻的G1变化过程中的稳定性 在分化过程中发生的？2)Cdt1许可因素如何运作以及如何控制？第三章 在细胞周期静止期的建立和维持过程中，许可是如何被阻断的？成功 回答这些问题将有助于阐明一个重要的生物过程，这是生物体的基础。 发育和体内平衡。此外，我们将研究细胞中的DNA复制和细胞周期控制， 这些设置尚未被探索，以揭示细胞增殖的全新方面 控制

项目成果

Efficiency and equity in origin licensing to ensure complete DNA replication.

• DOI: 10.1042/bst20210161
• 发表时间: 2021-11-01
• 期刊: Biochemical Society transactions
• 影响因子: 3.9