MECHANISMS AND MACROMOLECULAR INTERACTIONS UNDERLYING CELLULAR RESPONSES TO STRESS SIGNALS

细胞对应激信号反应的机制和大分子相互作用

• 批准号: 10570860
• 负责人: Alexandra M. Deaconescu
• 金额: $ 39.88万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570860
• 关键词: Address; Affect; Age; Antibiotics; Antimicrobial Resistance; Area; Bacteria sigma factor KatF protein; Biology; COVID-19 pandemic; Catalysis; Collaborations; Collection; Combination Drug Therapy; Coupled; Coupling; DNA; DNA Damage; DNA Repair; DNA-Directed RNA Polymerase; Development; Dissection; Environment; Evolution; Genetic Transcription; Genomics; Infection; Lesion; Mediating; Modality; Molecular Evolution; Mutagenesis; Nature; Nucleotide Excision Repair; Organism; Pathway interactions; Process; Proteins; Proteolysis; Public Health; Reagent; Regulation; Research; SOS Response; Signal Transduction; Specificity; Stress; Structural Biochemistry; Transcription Elongation; Transcription Initiation; Transcription-Coupled Repair; Work; antimicrobial; biological adaptation to stress; cross immunity; novel; pathogen; programs; promoter; recruit; repaired; response; stressor; structural biology; transmission process

PROJECT SUMMARY Proteins carrying out DNA repair, replication and transcription, processes essential for the stable transmission and expression of genomic information, share the same track – the DNA – and require delicate coordination to achieve their function. Often, regulation of these processes occurs at the level of targeting or well-timed recruitment, but also catalysis and even turnover of the factor in question. We will address these three principal modalities of regulation in the context of bacterial responses to stress signals. Our questions and hypotheses are grouped into two large areas, (1) regulation of the general stress response mediated by the promoter specificity subunit RpoS; this is exemplary of a general stress response mechanism that affect transcription initiation, and (2) specific responses to DNA damage such as subpathways of nucleotide excision repair; these are exemplary of how the DNA damage response interfaces with transcription elongation, termination as well as replication. The principal questions that will be addressed by my research plan are: A. How are activating and inhibitory regulatory inputs integrated to tune the RpoS core pathway and globally reprogram transcription in response to an adverse environment? How does the ClpXP adaptor RssB and stress-specific ClpXP anti-adaptors tune the proteolysis of RpoS in a stress-specific manner? B. What are the mechanisms for preferential recruitment of the NER machinery to specific lesions, or to the template strand, directly read by RNA polymerase? How is the availability of early NER factors regulated by proteolysis in the context of DNA damage and transcription-coupled DNA repair? How and when do transcription-repair coupling factors collaborate with key players in the SOS response to promote mutagenesis? Can we leverage these mechanisms towards developing novel anti-evolution drugs for combination therapies against infection with diverse pathogens? Previous work has already allowed us to build a critical collection of reagents and expertise in the structural biology and biochemistry of transcription-coupled repair and RpoS biology. This gives us now an excellent entry point for a mechanistic dissection of the processes listed above and the development of novel antimicrobial strategies. The significance of our work is thus not only fundamental and conceptual in nature, but has immediate applications in controlling the worldwide public health crisis of antimicrobial resistance, particularly in the age of the COVID-19 pandemic.

项目摘要 进行DNA修复，复制和转录的蛋白质对于稳定传播必不可少的过程 和基因组信息的表达，共享相同的轨道 - DNA - 需要精致的协调 实现其功能。通常，这些过程的调节发生在定位级别或定时的级别 招募，但也催化甚至是有关因素的流失。我们将向这三位校长讲话 在细菌对压力信号反应的背景下，调节的方式。我们的问题和假设 分为两个大区域，（1）调节启动子介导的一般应力反应 特异性亚基RPO；这是影响转录的一般应力反应机制的典范 启动，以及（2）对DNA损伤的具体反应，例如核苷酸惊喜修复的子路；这些 是DNA损伤响应如何与转录伸长，终止以及 复制。我的研究计划将解决的主要问题是： 答：如何整合激活和抑制性调节输入，以调整RPOS核心途径和 响应不利环境的全球重编程转录？ clpxp如何 适配器RSSB和应力特异性CLPXP抗适应器在应力特异性中调节RPO的蛋白水解 方式？ B.优先募集NER机械为特定病变的机制， 还是直接通过RNA聚合酶读取的模板链？早期的可用性如何 在DNA损伤和转录偶联DNA修复的背景下，由蛋白水解调节的因素？ 转录修复耦合因素如何以及何时与SOS响应中的主要参与者合作 促进诱变？我们可以利用这些机制来发展新的反进化 用于与潜水病原体感染的组合疗法的药物？ 以前的工作已经使我们能够建立关键的试剂和结构中的专业知识 转录耦合修复和RPOS生物学的生物学和生物化学。这为我们提供了一个很好的条目 对上述过程的机理解剖和新型抗菌剂的发展的点 策略。因此 在控制全球抗菌素抵抗的全球公共卫生危机中的应用，特别是在 19009年大流行。