Cell Cycle Dynamics that Ensure Genome Maintenance

确保基因组维护的细胞周期动力学

• 批准号: 10441332
• 负责人: Jeanette Gowen Cook
• 金额: $ 57.53万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441332
• 关键词: Address; Aging; Architecture; Biochemistry; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Proliferation; Cells; Chromatin; Companions; Competence; Complex; DNA; DNA Repair; DNA biosynthesis; DNA replication fork; DNA replication origin; Defect; Development; Diagnosis; Diagnostic; Ensure; Environment; Event; Future; G1 Phase; Genome; Genomic Instability; Goals; Human; Knowledge; Length; Licensing; Maintenance; Malignant Neoplasms; Mammalian Cell; Molecular; Molecular Genetics; Oncogene Activation; Outcome; Pathology; Pathway interactions; Precision therapeutics; Regenerative Medicine; Regulation; Replication Initiation; Research; S phase; Stream; Testing; Work; cancer therapy; cooking; extracellular; genomic locus; helicase; innovation; insight; mammalian genome; molecular dynamics; programs; single cell analysis; success; tissue degeneration; tool; tumorigenesis

CELL CYCLE CONTROLS THAT ENSURE GENOME MAINTENANCE (COOK) SUMMARY Our research program seeks insight into the fundamental architecture and regulation of the human cell division cycle, with specific focus on DNA replication competence. Complete and efficient duplication of an entire mammalian genome requires that many thousands of DNA replication origins become licensed in G1 phase through the DNA loading of MCM helicase complexes. Loaded MCM complexes render genomic loci competent for replication initiation during S phase. Loss of normal origin licensing control causes genome instability, which can cause oncogenesis, developmental defects, and degeneration. Origin licensing control is as important for ensuring normal genome maintenance as companion mechanisms such as replication fork control and stability or DNA repair, but the regulation of origin licensing is only partly understood. For example, how is complete origin licensing achieved in cells with dramatically different G1 lengths, such as during development or after oncogene activation? How is origin licensing activity distributed in a heterogenous chromatin environment? How is origin licensing controlled during transitions into and out of the cell cycle? These unanswered questions preclude the comprehensive understanding of proliferation control needed to diagnose and treat pathologies in which cell proliferation is a hallmark. Our long-term goal is to understand how DNA replication origin licensing is governed by intracellular and extracellular pathways that control proliferation and development and to understand the outcomes of perturbations to those controls. Our current and future projects are organized into scientific questions clustered into two central goals: Goal 1) Define how MCM loading dynamics regulate G1 progression, Goal 2) Determine the molecular events that establish and maintain cell cycle exit to quiescence. In recent years, we developed innovative experimental tools and approaches using quantitative live cell and fixed single cell analyses in cultured human cells. We combine these tools with molecular genetics and biochemistry. We focus on uncovering molecular mechanisms and their inter-relationships, and then test the consequences of perturbing those mechanisms. Our prior efforts produced a consistent stream of basic scientific discoveries and advances for both the field and the scientific workforce. The impacts of success towards our central goals are to define previously unexplored mechanisms in the mammalian cell cycle and to probe the dynamics of molecular events required for genome maintenance.

细胞周期控制可确保基因组维持（COCK） 概括 我们的研究计划寻求深入了解的基础架构和监管 人类细胞分裂周期，特别关注DNA复制能力。完成和 整个哺乳动物基因组的有效重复需要数千种DNA 通过MCM解旋酶的DNA负载，复制起源在G1阶段获得许可 复合物。加载的MCM复合物使基因组基因座有能力进行复制启动 在s阶段。正常起源许可控制的丧失会导致基因组不稳定性，这可以 导致肿瘤发生，发育缺陷和变性。来源许可控制是 确保正常基因组维持作为伴侣机制（例如） 复制叉控制和稳定性或DNA修复，但原点许可的调节只是 部分理解。例如，如何在单元格中获得完整的起源许可 G1的长度急剧不同，例如在发育期间还是癌基因激活后？ 原始许可活动如何分布在异源染色质环境中？怎么了 在过渡进出细胞周期期间控制的原点许可？这些没有回答 问题排除了对所需的扩散控制的全面理解 诊断和治疗细胞增殖是标志的病理。 我们的长期目标是了解DNA复制起源许可如何受 细胞内和细胞外途径控制增殖和发育以及 了解对这些控件的扰动结果。我们当前和未来的项目是 组织成科学问题，聚集在两个核心目标中：目标1）定义MCM 加载动力学调节G1进展，目标2）确定分子事件 建立并维持细胞周期出口到静止。近年来，我们开发了创新 实验工具和方法使用定量活细胞和固定单细胞分析 培养的人类细胞。我们将这些工具与分子遗传学和生物化学相结合。我们 专注于发现分子机制及其相互关系，然后测试 扰动这些机制的后果。我们先前的努力产生了一致的流 该领域和科学劳动力的基本科学发现和进步。这 成功对我们的中心目标的影响是定义以前未开发的机制 在哺乳动物细胞周期中，探测基因组所需的分子事件的动力学 维护。