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: 10330653
• 负责人: Alexandra M. Deaconescu
• 金额: $ 39.84万
• 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/10330653
• 关键词: Address; Affect; Age; Antibiotics; Antimicrobial Resistance; Area; Bacteria sigma factor KatF protein; Biology; COVID-19 pandemic; Catalysis; 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 Process; Transcription-Coupled Repair; Work; antimicrobial; biological adaptation to stress; cross immunity; novel; pathogen; 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类，这些过程对稳定传播至关重要 基因组信息的表达，共享同一个轨道-DNA -并需要微妙的协调， 实现其功能。通常，这些过程的调节发生在目标或适时的水平上。 招聘，而且也催化，甚至在问题的因素营业额。我们将讨论这三个主要问题， 在细菌对应激信号反应的背景下的调节方式。我们的问题和假设 分为两个大的领域，（1）由启动子介导的一般应激反应的调节 特异性亚基RpoS;这是影响转录一般应激反应机制的示例 启动，和（2）对DNA损伤的特异性反应，如核苷酸切除修复的子途径;这些 是DNA损伤反应如何与转录延伸、终止以及 复制的我的研究计划将解决的主要问题是： A.激活和抑制性调节输入如何整合以调节RpoS核心途径， 在全球范围内重新编程转录以应对不利的环境？ClpXP如何 衔接子RssB和应激特异性ClpXP抗衔接子在应激特异性的 举止？ B。什么是优先募集NER机制到特定病变的机制， 还是模板链，直接被RNA聚合酶读取？如何获得早期净入学率 在DNA损伤和转录偶联DNA修复的背景下，蛋白水解调节的因素？ 转录修复偶联因子如何以及何时与SOS反应中的关键参与者合作 来促进突变吗我们能否利用这些机制来开发新的反进化 针对不同病原体感染的联合治疗药物？ 以前的工作已经使我们能够建立一个关键的收集试剂和专业知识的结构 转录偶联修复的生物学和生物化学以及RpoS生物学。这给了我们一个很好的切入点 对上述过程的机理剖析和新型抗菌剂的开发 战略布局因此，我们工作的意义不仅是根本性的和概念性的，而且具有直接的意义。 在控制全球范围内的抗菌素耐药性公共卫生危机方面的应用，特别是在 COVID-19大流行。