Novel mechanisms of DNA repair and cell cycle regulation in bacteria

细菌 DNA 修复和细胞周期调控的新机制

基本信息

批准号：
10559506
负责人：
Lyle Simmons
金额：
$ 37.31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559506
关键词：
Affect Antibiotic Resistance Antibiotic Therapy Bacillus subtilis Bacteria Bacterial Antibiotic Resistance Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cell Proliferation Cell Proliferation Regulation Cells DNA DNA Damage DNA Repair DNA Repair Pathway DNA Sequence Rearrangement DNA damage checkpoint Defect Disease Disinfectants Economic Burden Environment Excision Repair Exposure to Genes Genome Goals Gram-Positive Bacteria Growth Healthcare Healthcare Systems Hospitals Human Impairment Lead Listeria monocytogenes Malignant Neoplasms Medicine Mutation Nosocomial Infections Organism Pathway interactions Process Proliferating Proteins Recovery Research Source Stress United States antimicrobial care burden clinically relevant coping environmental stressor experimental study gene product genome integrity genome-wide human pathogen methicillin resistant Staphylococcus aureus novel pathogen pathogenic bacteria repaired response

项目摘要

Project Summary: A major problem in medicine today is the emergence and persistence of antibiotic resistant bacteria. Although bacteria have evolved several strategies to grow in harsh environments, many bacterial species broadly cope in unfavorable conditions by regulating growth and through inducing DNA damage responses. In fact, all organisms respond to DNA damage by enlisting DNA repair pathways and by regulating cell cycle progression. Bacterial cells are constantly exposed to a broad spectrum of DNA damage caused by intracellular sources, environmental stressors, antibiotic treatments, and disinfectants applied in hospital settings. Although DNA repair and cell cycle checkpoints have been well studied in some bacteria, far less is known about these processes in Gram-positive bacteria. One major challenge is that even for the most well studied Gram-positive bacterium, Bacillus subtilis, almost half of the genes in the genome are of unknown function, representing a critical and fundamental gap in our understanding of how these bacteria mitigate stress that affects growth and proliferation. While Bacillus subtilis does not cause disease, it is closely related to a number of important human pathogens, including Methicillin-resistant Staphylococcus aureus, Listeria monocytogenes and several other pathogens that are responsible for many hospital-acquired infections, which impose significant economic burdens on our healthcare system annually. Therefore, it is important to understand how a broad group of clinically relevant bacteria respond to DNA damage and regulate cell proliferation. The long-term goal of this research is to understand the contribution of unstudied genes and novel mechanisms to DNA repair and cell cycle regulation in Gram-positive bacteria. We used large-scale genome-wide approaches to identify several uncharacterized genes that are highly conserved among Gram-positive bacteria and critical for DNA repair and regulation of cell proliferation. Two of these gene products define a new DNA excision repair pathway while four other genes are critical for DNA damage checkpoint recovery, allowing cells to re-enter the cell cycle after the damage has been repaired. We expand these experiments to continue to identify novel interactions with regulatory partners that control initiation timing and cell proliferation. We expect these studies will result in the complete mechanistic characterization of proteins involved in initiation, DNA repair, and cell cycle checkpoints. All of the genes we propose to study are either essential or cause severe growth defects when impaired, underscoring their importance as possible targets for novel antimicrobial therapies.

项目概要：当今医学的一个主要问题是抗生素耐药性细菌的出现和持续存在。虽然细菌已经进化出多种在恶劣环境中生长的策略，许多细菌物种广泛应对在不利条件下通过调节生长和诱导 DNA 损伤反应。事实上，所有生物体通过利用 DNA 修复途径和调节细胞周期进程来应对 DNA 损伤。细菌细胞不断暴露于由细胞内来源引起的广泛 DNA 损伤，环境压力源、抗生素治疗和医院环境中使用的消毒剂。虽然DNA 修复和细胞周期检查点已在某些细菌中得到充分研究，但人们对这些知之甚少革兰氏阳性菌中的过程。一个主要的挑战是，即使对于研究最深入的革兰氏阳性菌来说，细菌，枯草芽孢杆菌，基因组中几乎一半的基因功能未知，代表了我们对这些细菌如何减轻影响生长和发育的压力的理解存在关键和根本的差距增殖。虽然枯草芽孢杆菌不会引起疾病，但它与许多重要的疾病密切相关。人类病原体，包括耐甲氧西林金黄色葡萄球菌、单核细胞增多性李斯特菌和多种其他病原体导致许多医院获得性感染，这对经济造成重大影响每年给我们的医疗保健系统带来负担。因此，了解广泛的群体如何临床相关细菌对 DNA 损伤做出反应并调节细胞增殖。本次活动的长远目标研究的目的是了解未研究的基因和新机制对 DNA 修复和细胞的贡献革兰氏阳性菌的循环调节。我们使用大规模全基因组方法来识别几个未表征的基因在革兰氏阳性细菌中高度保守，对 DNA 修复和修复至关重要细胞增殖的调节。其中两个基因产物定义了新的 DNA 切除修复途径，同时另外四个基因对于 DNA 损伤检查点恢复至关重要，使细胞能够在修复后重新进入细胞周期。损坏已修复。我们扩展这些实验以继续识别与控制起始时间和细胞增殖的监管伙伴。我们预计这些研究将导致参与起始、DNA 修复和细胞周期检查点的蛋白质的完整机制表征。我们建议研究的所有基因要么是必需的，要么在受损时导致严重的生长缺陷，强调它们作为新型抗菌疗法的可能靶标的重要性。