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Initiation of DNA Replication at Cell Origins in Yeast

酵母细胞起源处 DNA 复制的起始

基本信息

批准号：
7844930
负责人：
BRUCE W. STILLMAN
金额：
$ 64.49万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844930
关键词：
ATP phosphohydrolase Applications Grants Area Award Binding Biochemical Biochemistry Biological Models Cell Cycle Cell physiology Cells Cellular biology Chromatin Chromatin Modeling Chromatin Structure Chromosome Structures Chromosomes Complex Cyclin-Dependent Kinases DNA DNA Repair DNA Replication Timing DNA biosynthesis DNA replication origin DNA-Binding Proteins DNA-Directed DNA Polymerase Diagnosis Disease Docking Epigenetic Process Eukaryota Eukaryotic Cell Forms Controls Funding G1 Phase Gene Expression Gene Silencing Generations Genes Genetic Genetic Screening Genome Genome Stability Genomic Instability Goals Human Interruption Knowledge Laboratories Lead Learning Link Location MCM Protein MCM4 gene Maintenance Malignant Neoplasms Metabolism Modeling Neoplastic Cell Transformation Organized by Structure Protein Phase Transition Postdoctoral Fellow Pre-Replication Complex Process Protein Kinase Proteins Recruitment Activity Regulation Replication Initiation Research Research Support Rest Role Saccharomyces cerevisiae Series Site Specific qualifier value Stochastic Processes System Therapeutic Intervention Time Work Yeasts cancer cell career chromatin assembly factor I in vivo mutant nucleotide metabolism origin recognition complex structural biology

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to determine the mechanism and regulation of the initiation of DNA replication in eukaryotic cells. It is clear that for maintenance of the integrity of the genome from one cell generation to the next, DNA and its associated chromatin structures must be duplicated in a highly controlled and accurate manner. Interruption of these controls may promote genome instability and lead to neoplastic transformation. Moreover, the DNA replication proteins represent tangible targets for therapeutic intervention and diagnosis of proliferation of cancer cells, and other proliferative disorders. The initiator protein (ORC) cooperates with a series of DNA replication proteins, including Cdc6 to establish at origins of DNA replication a complex that allows later initiation of DNA synthesis at each origin. The initiator protein is a multi-subunit, ATP-dependent DNA binding protein that cooperates with another ATPase, Cdc6. The proposed research in this application will investigate, using the yeast S. cerevisiae, how DNA replication occurs in an ORC- and origin-dependent manner and how initiation of DNA replication and chromatin inheritance is temporally controlled throughout the cell division cycle. In specific aim 1, the biochemical mechanisms of initiation of DNA replication will be investigated. In specific aim 2, the role of the Cdc7-Dbf4 (DDK) protein kinase in the control of initiation of DNA and other processes will be studied. In specific aim 3, the role of the DNA polymerase clamp loader PCNA will be investigated in chromatin inheritance and genomic stability, including the role of dNTP metabolism in this process.The inheritance of the genome involves copying the DNA and the associated protein structures that organize chromosome structure and control gene expression. These processes have to be highly accurate because any errors that occur can lead to genome instability and progression toward cancer. The research involves study of the mechanism and control of genome duplication in yeast cells as a model for how this occurs in human cells.

描述(申请人提供)：本研究的目标是确定真核细胞中DNA复制的启动机制和调控。显然，为了从一代细胞到下一代细胞保持基因组的完整性，DNA及其相关的染色质结构必须以高度受控和准确的方式复制。这些调控的中断可能会促进基因组的不稳定，并导致肿瘤转化。此外，DNA复制蛋白是治疗干预和诊断癌细胞增殖和其他增殖性疾病的有形靶点。启动子蛋白(ORC)与包括CDC6在内的一系列DNA复制蛋白合作，在DNA复制的起始处建立一个复合体，允许在每个起始处随后启动DNA合成。启动子蛋白是一种依赖于ATP的多亚基DNA结合蛋白，与另一种ATPase CDC6协同作用。这项应用中的拟议研究将使用酿酒酵母来研究DNA复制是如何以依赖于ORC和来源的方式发生的，以及DNA复制和染色质遗传的启动如何在整个细胞分裂周期中受到时间控制。在特定的目标1，将研究启动DNA复制的生化机制。在具体目标2中，将研究CDC7-Dbf4(DDK)蛋白激酶在控制DNA启动和其他过程中的作用。在具体目标3中，将研究DNA聚合酶钳夹载体--增殖细胞核抗原在染色质遗传和基因组稳定性中的作用，包括dNTP代谢在这一过程中的作用。基因组的遗传涉及复制DNA和相关的蛋白质结构，这些结构组织染色体结构和控制基因表达。这些过程必须非常准确，因为发生的任何错误都可能导致基因组不稳定和向癌症发展。这项研究包括研究酵母细胞中基因组复制的机制和控制，以此作为在人类细胞中发生这种情况的模型。