Molecular mechanisms of nucleic acid recognition and maintenance in meiosis and innate immunity

减数分裂和先天免疫中核酸识别和维持的分子机制

• 批准号: 10330658
• 负责人: Kevin Daniel Corbett
• 金额: $ 46.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330658
• 关键词: ATP phosphohydrolase; Adopted; Architecture; Area; Bacteria; Cell division; Chromosome Structures; Chromosomes; Circular DNA; Communities; Complex; DNA; DNA Binding; DNA Repair; Disease; Educational process of instructing; Eukaryota; Evolution; Fellowship; Generations; Genes; Genetic Recombination; Genome; Genomic DNA; Germ Cells; Grant Review; Haploidy; Homologous Gene; Immune; Innate Immune System; Knowledge; Laboratories; Maintenance; Malignant Neoplasms; Meiosis; Messenger RNA; Mitosis; Molecular; Molecular Machines; NIH Center for Scientific Review; Natural Immunity; Nerve Degeneration; Nucleic Acids; Organism; Pathogenicity; Plasmids; Prokaryotic Cells; Proteins; RNA; RNA-Binding Proteins; Research; Role; Science; Sexual Reproduction; Signaling Protein; Structural Biologist; Structure; System; Translations; United States National Institutes of Health; Virus; Work; assault; cohesin; condensin; fascinate; genome integrity; interest; mid-career faculty; novel; programs; recruit; viral RNA

PROJECT SUMMARY Molecular mechanisms of nucleic acid recognition and maintenance in meiosis and innate immunity I am a biochemist and structural biologist with a strong interest in the molecular mechanisms of genome maintenance. Since starting my own laboratory in 2011, I have made major contributions in the areas of chromosome organization and recombination in eukaryotic meiosis, in particular defining the molecular architecture and assembly mechanisms of the meiotic chromosome axis. My laboratory also determined the structure and mechanism of TRIP13, an ATPase regulator of HORMA domain signaling proteins in mitosis, meiosis, and DNA repair. As an Associate Professor and Vice Chair of the UC San Diego Biomedical Sciences graduate program, I contribute significantly to graduate teaching and advising. I am also active in the broader scientific community, having participated in grant review for NIH, graduate fellowship review for NSF, and having served on an NIH Center for Scientific Review workgroup in 2019-2020. My laboratory's work over the next five years will focus on a diverse but conceptually related set of questions in genome maintenance and protein-nucleic acid recognition. Our primary interest is in meiosis, the specialized two-stage cell division program that gives rise to haploid gametes and is crucial for sexual reproduction in eukaryotes. Building off our work defining the architecture of the chromosome axis, we will determine how the axis interacts with and controls the activity of DNA-binding cohesin complexes, and how the axis recruits and controls recombination proteins to drive the formation of inter-homolog crossovers. Next, we are pursuing collaborative projects to understand the structural basis for sequence- and structure-specific RNA recognition in two contexts. With Gene Yeo (UCSD), we are developing a new generation of programmable sequence-specific RNA binding proteins to target and degrade disease-associated mRNAs in diverse diseases from cancer to neurodegeneration. With Matt Daugherty (UCSD), we are determining how IFIT proteins in the mammalian innate immune system cooperate to specifically recognize viral RNAs and inhibit their translation. Finally, my laboratory has begun a new effort aimed at determining the molecular mechanisms of novel bacterial defense systems in which canonical genome-maintenance machines have adapted to new roles. In our first work in this area, we have found that the condensin/cohesin-like MksBEFG system protects its bacterial hosts from plasmid transformation by specifically recognizing and cleaving closed-circular DNA. I am fascinated by molecular machines, particularly those that maintain genome integrity in the face of constant internal and external assault. My research program is aimed at understanding the molecular basis for genome maintenance in diverse contexts, and in exploring how the proteins responsible for genome maintenance have adapted to new roles throughout evolution.

项目总结 减数分裂和天然免疫中核酸识别和维持的分子机制 我是一名生物化学家和结构生物学家，对基因组的分子机制非常感兴趣。 维修。自2011年成立自己的实验室以来，我在以下领域做出了重大贡献 真核细胞减数分裂中的染色体组织和重组，特别是确定分子 减数分裂染色体轴的结构和组装机制。我的实验室也确定了 有丝分裂中Horma结构域信号蛋白的ATPase调节子TRIP13的结构与机制 减数分裂和DNA修复。加州大学圣地亚哥分校生物医学科学副教授兼副主席 在研究生课程期间，我为研究生教学和咨询做出了重大贡献。我也活跃在更广泛的领域 科学界，参与了国家卫生研究院的拨款审查，国家科学基金会的研究生奖学金审查，以及 曾在2019-2020年间担任美国国立卫生研究院科学审查中心工作组成员。 我的实验室在未来五年的工作将集中在一组不同但概念上相关的 基因组维护和蛋白质-核酸识别中的问题。我们的主要兴趣是减数分裂，即 专门化的两阶段细胞分裂程序，产生单倍体配子，是有性生殖的关键 真核生物的繁殖。在我们定义染色体轴结构的工作的基础上，我们将 确定轴如何与DNA结合的粘连蛋白复合体相互作用并控制其活性，以及 Axis招募并控制重组蛋白，以驱动同源基因间交叉的形成。接下来，我们 正在进行合作项目，以了解特定序列和结构的RNA的结构基础 在两个背景下的识别。与吉恩·杨(UCSD)合作，我们正在开发新一代可编程 序列特异性RNA结合蛋白在不同疾病中靶向和降解疾病相关mRNAs 从癌症到神经退化。与马特·多尔蒂(UCSD)合作，我们正在确定IFIT蛋白质如何在 哺乳动物的先天免疫系统协同识别病毒RNA并抑制其翻译。 最后，我的实验室开始了一项新的努力，旨在确定新奇病毒的分子机制 细菌防御系统，其中规范的基因组维护机器已经适应了新的角色。在……里面 我们在这一领域的第一项工作，我们发现凝聚素/粘附素样蛋白BEFG系统保护其 细菌通过特异性识别和切割闭合环状DNA而转化为质粒。 我对分子机器着迷，特别是那些在面对 不断的内部和外部攻击。我的研究项目的目的是了解 在不同背景下的基因组维护，以及在探索蛋白质如何负责基因组 在整个进化过程中，维护已经适应了新的角色。