Growth and differentiation in Bacillus subtilis

枯草芽孢杆菌的生长和分化

• 批准号: 10404754
• 负责人: DAVID Z RUDNER
• 金额: $ 42.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404754
• 关键词: 3-Dimensional; ATP phosphohydrolase; Antibiotics; Bacillus subtilis; Bacteria; Biogenesis; Cell Wall; Cells; Cellular biology; Chromatin Loop; Chromosomes; Complex; Cytolysis; DNA; Defect; Differentiation and Growth; Disease; Ensure; Enzymes; Eukaryota; Failure; Goals; Growth; Human; Hydrolase; Knowledge; Link; Lipids; Maintenance; Malignant Neoplasms; Mediating; Molecular; Monitor; Morphology; Organism; Pathway interactions; Peptides; Peptidoglycan; Play; Polysaccharides; Process; Research; Resolution; Role; Shapes; Signal Transduction; Signal Transduction Pathway; Sister; Sister Chromatid; Site; System; Therapeutic Intervention; Walking; combat; condensin; crosslink; developmental disease; inorganic phosphate; insight; new therapeutic target; repaired; segregation; therapeutic development; virtual

PROJECT SUMMARY/ABSTRACT The proposed studies are part of our long-term effort to elucidate fundamental mechanisms underlying chromosome dynamics and bacterial envelope biogenesis in the bacterium Bacillus subtilis. Compaction of replicated chromosomes into morphologically and spatially distinct sister chromatids is essential for faithful DNA segregation in all organisms. The goal of our research is to broadly elucidate how B. subtilis organizes and segregates its chromosomes but we have placed particular emphasis on defining the activity and function of the broadly conserved SMC condensin complex in these processes. Our studies have revealed that these ring-shaped ATPases extrude DNA loops. Loop extrusion ensures that these complexes act in cis drawing DNA in on itself and away from its sister chromosome. This activity can explain how SMC complexes can resolve newly replicated origins in bacteria and sister chromatids in eukaryotes. Our future research seeks to establish whether loop extrusion mediates origin resolution and the extent to which it drives the dynamic rearrangements of the chromosome during the replication-segregation cycle. Separately, we will define the molecular basis for site-specific unloading of SMC complexes by XerD at the replication terminus. Analysis of chromosome dynamics in this simple bacterial system will provide mechanistic insight and a level of resolution not possible in more complex organisms. The bacterial cell wall peptidoglycan (PG) is composed of long glycan strands cross-linked together by short peptides. This three-dimensional meshwork protects the cell from osmotic lysis, determines shape, and its assembly is the target of some of our most successful antibiotics. Accordingly, a deeper understanding of cell wall biogenesis has broad implications for both basic bacterial cell biology and therapeutic development. Research over the last half century has identified virtually all the factors involved in envelope assembly. A major gap in our knowledge is how these enzymes are coordinated with each other and how the cell monitors the envelope for defects and directs their repair. Our future research is focused on three signal transduction pathways that play central roles in these processes. The WalR-WalK two-component signaling system is involved in the homeostatic control of cell wall hydrolases required for growth. The SigI-RsgI pathway monitors the cell wall meshwork and induces PG remodeling enzymes when it identifies defects. Finally, the SigM-YhdLK pathway monitors the universal lipid carrier undecaprenyl-phosphate and prioritizes its use for cell wall synthesis. We seek to define how these pathways function in molecular detail. Our findings will provide broadly relevant principles for envelope assembly and maintenance in all bacteria.

项目摘要/摘要 拟议的研究是我们阐明基本机制的长期努力的一部分 枯草芽孢杆菌中的染色体动力学和细菌包膜生物发生。 在形态学和空间上差异化染色单体的重复染色体的压实是 在所有生物体中忠实的DNA隔离至关重要。我们研究的目的是广泛阐明B. 枯草厂组织和分离其染色体，但我们特别强调定义 在这些过程中，广泛保守的SMC冷凝蛋白复合物的活性和功能。我们的研究有 揭示了这些环形ATPase挤压DNA环。循环挤出确保这些复合物 在独联体中绘制DNA本身，远离其姐妹染色体。这项活动可以解释SMC如何 复合物可以在真核生物中的细菌和姐妹染色单体中解析新复制的起源。我们的未来 研究试图确定循环挤出是否介导了原点分辨率及其驱动的程度 在复制 - 分离周期中染色体的动态重排。单独，我们会的 定义XERD在复制末端的SMC复合物的位点特异性卸载的分子基础。 在此简单细菌系统中对染色体动力学的分析将提供机械洞察力和水平 在更复杂的生物中不可能解决。 细菌细胞壁肽聚糖（PG）由短的聚糖链组成 肽。这种三维网状工作可保护细胞免受渗透裂解的影响，确定形状及其形状及其 组装是我们一些最成功的抗生素的目标。因此，对细胞的更深入了解 壁生物发生对碱性细菌细胞生物学和治疗发育都有广泛的影响。 过去半个世纪的研究几乎确定了信封装配中涉及的所有因素。一个 我们所知的主要差距是这些酶如何相互配位以及细胞监测器如何进行协调 缺陷的信封并指导其修复。我们未来的研究集中于三个信号转导 在这些过程中起着核心作用的途径。 WALR-WALK两个组件信号系统是 参与生长所需的细胞壁水解酶的体内平衡控制。 Sigi-Rsgi途径 监视细胞壁网状功能并在鉴定缺陷时诱导PG重塑酶。最后， SIGM-YHDLK途径监视通用脂质载体不依赖磷酸的通用脂质载体，并优先考虑其用于 细胞壁合成。我们试图定义这些途径如何在分子细节中发挥作用。我们的发现会 为所有细菌中的包膜组装和维护提供广泛相关的原理。