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Molecular mechanisms regulating cell cycle progression in Caulobacter crescentus

新月柄杆菌细胞周期进程的分子机制

基本信息

批准号：
7753631
负责人：
Lisa M. Bowers
金额：
$ 2.19万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2010-06-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753631
关键词：
Agriculture Anti-Bacterial Agents Antibiotics Antibodies Aspartate Bacteria Bacteriophages Binding Bioinformatics Biological Models Biological Warfare Biology Biomedical Engineering Biosensing Techniques Caulobacter Caulobacter crescentus Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Survival Cell division Cells Cellular biology Chimeric Proteins Complex Comprehension Coupled DNA biosynthesis Defect Drug Delivery Systems Essential Genes Eukaryotic Cell Flagella Genes Genetic Genetic Transcription Genome Hand Histidine Hybrids In Vitro Label Life Life Cycle Stages Location Logic Molecular Monitor Morphology Mutation Names Orthologous Gene Pathway interactions Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiologic pulse Prokaryotic Cells Property Proteins Proteobacteria Reaction Replication Origin Role Shapes Signal Transduction Site Source Surface Time Water Work cell motility chromosome replication daughter cell drug discovery in vivo insight loss of function mutant promoter protein-histidine kinase public health relevance reconstitution response small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): A fundamental question in biology is how one cell divides to yield two progeny with different identities. Like eukaryotic cells, bacteria undergo complex life cycles and often produce daughter cells with distinct shapes and properties. In this work, Caulobacter crescentus is used as a model system for the study of asymmetry coupled to the division cycle. In this bacterium, each division produces two morphologically distinct daughter cells, a non-motile cell with a stalk that attaches to surfaces and a motile swarmer cell with a flagellum that propels it through the water. The stalked cell immediately begins a new round of chromosome replication and division, but the swarmer cell is unable to initiate DMA replication until it differentiates into a stalked cell. This complex cell division cycle is orchestrated by a network of two-component signal transduction proteins. The response regulator CtrA is a transcription factor that controls the expression of many cell cycle- regulated genes but also blocks DNA replication by binding to the origin of replication. CtrA activity is required for cell viability but it must be temporarily eliminated in stalked cells to permit the initiation of chromosome replication. CtrA activity is indirectly opposed by the essential response regulator DivK. Phosphorylated DivK results in a decrease in CtrA activity, which ultimately allows chromosome replication in the stalked cell. Thus, phosphorylation of DivK is essential for viability. DivK is known to be activated by the histidine kinase (HK) DivJ but because DivJ is dispensible, DivK must be phosphorylated by another HK or small molecule phosphodonor in Caulobacter. We propose a whole-genome approach to identify other HKs that could participate in DivK phosphorylation. Specifically, we aim to delete the gene for each of the 59 non-essential HKs in combination with a divJ deletion. This approach has yielded a likely candidate which we have tentatively named DivM other candidates must still be ruled out. We also aim to characterize the terminal phenotype of cells lacking both DivJ and DivM, determine the location and activity of DivM during the cell cycle, and elucidate the phosphorylation pathway from DivM to DivK. PUBLIC HEALTH RELEVANCE: The work proposed here is integral to achieving a complete understanding of the regulatory cascade leading to cell-cycle progression and differentiation in Caulobacter. Comprehension of the regulatory cascade could have far-reaching implications because many of the mechanisms discovered in Caulobacter are conserved among other species with important roles in agriculture, biowarfare, biosensing, and bioengineering. In addition, elucidating the basic mechanisms involved in bacterial cell cycle progression will generate key insights into prokaryotic cell biology, which will in turn help to identify new targets for antibacterial drug discovery.

描述(申请人提供)：生物学中的一个基本问题是一个细胞如何分裂以产生两个不同身份的后代。像真核细胞一样，细菌经历了复杂的生命周期，经常产生具有不同形状和特性的子细胞。在这项工作中，新月藻被用作一个模型系统来研究与分裂周期相耦合的不对称性。在这种细菌中，每个分裂产生两个形态上不同的子细胞，一个不活动的细胞，其茎附着在表面上，以及一个活动的沼泽细胞，其鞭毛推动它在水中穿行。被柄细胞立即开始新一轮的染色体复制和分裂，但沼泽细胞在分化成被柄细胞之前无法启动DMA复制。这个复杂的细胞分裂周期是由一个由两种信号转导蛋白组成的网络编排的。反应调节因子CtrA是一种转录因子，它控制许多细胞周期调控基因的表达，但也通过与复制起点结合来阻止DNA复制。CTRA活性是细胞存活所必需的，但在有柄的细胞中必须暂时消除它，才能启动染色体复制。CTRA活性间接地受到基本反应调节因子DivK的反对。磷酸化的DivK导致CtrA活性降低，最终允许染色体在茎细胞中复制。因此，DivK的磷酸化对细胞的存活至关重要。已知DivK被组氨酸激酶(HK)DivJ激活，但由于DivJ是必需的，所以DivK必须被另一个HK或Caulbacter中的小分子磷酸盐磷酸化。我们提出了一种全基因组的方法来识别其他可能参与DivK磷酸化的HKS。具体地说，我们的目标是删除59个非必需HKS的基因，并同时删除divJ。这种方法已经产生了一个可能的候选人，我们暂时将其命名为Divm，其他候选人仍然必须被排除。此外，我们还研究了缺乏DivJ和DivM的细胞的终末表型，确定了DivM在细胞周期中的位置和活性，并阐明了从DivM到DivK的磷酸化途径。公共卫生相关性：这里提出的工作是实现对导致细胞周期进展和分化的调节级联的完整了解的不可或缺的一部分。对调控级联的理解可能具有深远的影响，因为在硫杆菌中发现的许多机制在农业、生物仓库、生物传感和生物工程中具有重要作用的其他物种中是保守的。此外，阐明细菌细胞周期进程的基本机制将产生对原核细胞生物学的关键见解，这反过来将有助于确定抗菌药物发现的新靶点。