Stationary phase mutagenesis, a component of cell differentiation

静止期诱变，细胞分化的一个组成部分

• 批准号: 8689699
• 负责人: Eduardo A Robleto
• 金额: $ 33.89万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689699
• 关键词: Address; Affect; Animals; Antibiotic Resistance; Award; Bacillus subtilis; Bacteria; Binding; Biomedical Research; Bypass; Cannibalism; Cell Differentiation process; Cell Fraction; Cell physiology; Cells; Cellular Stress; ChIP-seq; Chronic Disease; Competence; Coupling; DNA; DNA Binding; DNA Repair; Degenerative Disorder; Development; Disease; Dose; Elements; Event; Evolution; Genes; Genetic; Genetic Load; Genetic Recombination; Genetic Transcription; Genetic Variation; Genome; Genomics; Goals; Health; Human; Immune response; Killer Cells; Knowledge; Malignant Neoplasms; Measures; Mediating; Microbe; Microbial Biofilms; Modeling; Molecular; Mutagenesis; Mutation; Pathologic Mutagenesis; Phase; Point Mutation; Population; Process; Production; Recruitment Activity; Relative (related person); Research; Research Infrastructure; Research Subjects; Research Support; Risk; SOS Response; Shapes; Stationary Populations; Stress; System; Testing; Transcription Process; Transcription-Coupled Repair; experience; extracellular; genome-wide; graduate student; human disease; improved; interest; meetings; next generation sequencing; novel; pathogen; pathogenic bacteria; public health relevance; repaired; research study; response; therapeutic target; transcription factor; tumor; undergraduate student

DESCRIPTION (provided by applicant): Our knowledge of mutagenic processes in cells experiencing stress or non-replicating conditions is limited and controversial. While it is well established that stressed cells activate mechanisms that increase mutagenesis, it remains unclear how these mechanisms bias mutagenesis towards the formation of beneficial mutations that allow cells to escape stress. One consequence of genome-wide hypermutation is the increased risk of genetic load; the point at which increased mutation render cells non-viable. An interesting idea that addresses this dilemma, and the subject of this research, is that a stressed population of cells reduces the risks associated with hypermutable states by differentiating a subpopulation of cells that promotes genetic diversity. These mechanisms producing this kind of mutations are conserved and inform on novel views on the evolutionary process. These processes are also implicated in the acquisition of antibiotic resistance and bypass of the immune response in pathogenic bacteria. In differentiated animal cells, these processes are both beneficial and detrimental. One, they produce genetic diversity, and two they associate with the development of tumors and degenerative diseases. The overall goal of this application is to gain a better understanding on how a population of stressed cells activates cellular mechanisms that produce genetic diversity. The hypothesis under study is that the development of competence (a.k.a. the K- state) in combination with the process of transcription and the transcription-repair coupling factor (TRCF - this factor biases DNA repair systems towards highly transcribed regions) mediates the formation of a cell subpopulation that promotes mutagenesis in B. subtilis. We test this hypothesis using genetic and genomic approaches that examine the accumulation of mutations in stressed cells that develop into the K-state and compare it to non-K cells. The genetic approach uses constructs that experimentally control the development of the K-state and transcription of a gene marker to measure mutagenesis. The genomic approach examines how natural development of the K-state and transcriptional responses during stress shape genomic mutation. Ultimately, this application examines a novel mutagenic mechanism and how it remodels the genome and promotes evolution in response to stress. The long term human health implications of this project are that it studies potential therapeutic targets for the treatment of degenerative and pathogenic diseases.

描述（由申请人提供）：我们对经历应激或非复制条件的细胞中的致突变过程的了解有限且存在争议。虽然已经确定应激细胞激活增加诱变的机制，但仍不清楚这些机制如何使诱变偏向于形成允许细胞逃避应激的有益突变。全基因组超突变的一个后果是遗传负荷的风险增加;突变增加使细胞无法存活的点。解决这一困境的一个有趣的想法，以及这项研究的主题，是一个有压力的细胞群体通过分化促进遗传多样性的细胞亚群来降低与超变状态相关的风险。这些产生这种突变的机制是保守的，并为进化过程提供了新的观点。这些过程也涉及获得抗生素耐药性和绕过病原菌的免疫反应。在分化的动物细胞中，这些过程既有益又有害。第一，它们产生遗传多样性，第二，它们与肿瘤和退行性疾病的发展有关。该应用程序的总体目标是更好地了解应激细胞群如何激活产生遗传多样性的细胞机制。研究的假设是，能力的发展（a.k.a. K-状态）与转录过程和转录修复偶联因子（TRCF -该因子使DNA修复系统偏向高度转录的区域）结合介导促进B中诱变的细胞亚群的形成。枯草杆菌。我们使用遗传和基因组方法来检验这一假设，这些方法检查了发展成K状态的应激细胞中突变的积累，并将其与非K细胞进行比较。遗传方法使用实验控制K状态的发展和基因标记物的转录的构建体来测量诱变。基因组方法研究了K状态的自然发展和应激过程中的转录反应如何形成基因组突变。最终，该应用程序研究了一种新的诱变机制，以及它如何重塑基因组并促进进化以应对压力。该项目对人类健康的长期影响是，它研究了治疗退行性和致病性疾病的潜在治疗靶点。