The Spatial and Temporal Integration of Chromosome Segregation and Cytokinesis

染色体分离和细胞分裂的时空整合

• 批准号: 8125755
• 负责人: Paola E Mera
• 金额: $ 4.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125755
• 关键词: Bacteria; Bacterial Proteins; Biochemical; Caulobacter; Caulobacter crescentus; Cell Cycle; Cell Cycle Progression; Cell division; Cells; Chromosome Segregation; Chromosomes; Cleaved cell; Cytokinesis; DNA; Defect; Development; Drug Delivery Systems; Engineering; Eukaryota; Event; Generations; Genetic; Goals; Human; Image; Lead; Malignant Neoplasms; Mediating; Organism; Prokaryotic Cells; Proteins; Replication Initiation; Research; Resolution; Role; Scheme; Signal Transduction; Site; Structure; Study models; Variant; Work; antimicrobial drug; chromosome replication; daughter cell; imaging modality; mutant; novel; prevent; protein function; segregation

DESCRIPTION (provided by applicant): Progression through the cell cycle requires exquisite coordination between DNA replication initiation and the multiple events that must take place in a timely and spatially-specific manner. Proteins involved in replication initiation are remarkably similar in eukaryotes and prokaryotes. Decades of research revealed in fine detail how these proteins function to initiate replication. However, it is becoming increasingly apparent that these proteins also mediate non-replication functions. Little is known about how these functions are coordinated with chromosome replication. The goal of this proposal is to define the mechanisms that integrate multiple cell cycle functions in Caulobacter crescentus, specifically focusing on the bacterial protein responsible for replication initiation, DnaA. Caulobacter is an ideal model for studying bacterial cell cycle regulatory circuitry due to the simultaneous replication and polar segregation of its single chromosome and its asymmetric cell division. Recently, a dnaA mutant that disrupts the coordination of chromosome replication and spatial/temporal control of cytokinesis was identified. The specific aims of this proposal are to determine the role of DnaA in mediating (a) nucleoid occlusion at the incipient division site and (b) the coordination of chromosomal segregation with division site selection using high-resolution imaging combined with engineered strains with specific fluorescent tags and key cell division protein depletions. PUBLIC HEALTH RELEVANCE: Cell division entails exquisite coordination of multiple events involved in cell cycle progression. In human, erroneous coordination of these events can cause fatal developmental defects including cancer. A clear understanding of the mechanisms used by bacteria to accomplish such exquisite coordination can reveal common schemes used across evolutionary diverse organisms, including human.

描述（由申请人提供）：细胞周期的进展需要DNA复制起始和必须以及时和空间特异性方式发生的多个事件之间的精密协调。真核生物和原核生物中参与复制起始的蛋白质非常相似。几十年的研究揭示了这些蛋白质如何启动复制的细节。然而，越来越明显的是，这些蛋白质也介导非复制功能。关于这些功能如何与染色体复制协调，我们知之甚少。该提案的目标是定义在新月柄杆菌中整合多种细胞周期功能的机制，特别关注负责复制起始的细菌蛋白DnaA。柄杆菌是研究细菌细胞周期调控的理想模型，因为它的单染色体同时复制和极性分离以及其不对称的细胞分裂。最近，一个dnaA突变体，破坏协调染色体复制和空间/时间控制的胞质分裂被确定。本提案的具体目的是确定DnaA在介导（a）初始分裂位点处的类核封闭和（B）染色体分离与分裂位点选择的协调中的作用，所述染色体分离与分裂位点选择使用高分辨率成像结合具有特异性荧光标签和关键细胞分裂蛋白缺失的工程菌株。 公共卫生相关性：细胞分裂需要细胞周期进程中涉及的多个事件的精密协调。在人类中，这些事件的错误协调可能导致致命的发育缺陷，包括癌症。清楚地了解细菌用来完成这种精致协调的机制可以揭示包括人类在内的进化多样性生物体使用的共同方案。