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: 10542438
• 负责人: Kevin Daniel Corbett
• 金额: $ 48.66万
• 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/10542438
• 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 Crossing Over; Genetic Recombination; Genome; Genomic DNA; Germ Cells; Grant Review; Haploidy; 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; segregation; 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.

项目摘要 减数分裂和先天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有浓厚的兴趣 维护。自2011年成立自己的实验室以来，我在该领域做出了重大贡献 真核减数分裂的染色体组织和重组，特别是定义分子 减数分裂染色体轴的结构和装配机制。我的实验室还确定了 Trip13的结构和机理，丝质蛋白的ATPase调节剂在有丝分裂中的ATPase调节剂， 减数分裂和DNA修复。作为加州大学圣地亚哥分校生物医学分校的副教授兼副主席 研究生课程，我为研究生教学和建议做出了重大贡献。我也很活跃 科学界，参加了NIH的赠款审查，NSF的研究生奖学金审查以及 在2019 - 2020年在NIH科学审查工作组中任职。 我实验室在未来五年内的工作将集中在一套多样化但概念上相关的一组 基因组维持和蛋白质核酸识别的问题。我们的主要兴趣是减数分裂， 专门的两阶段细胞分区程序会导致单倍配子，并且对性至关重要 真核生物的繁殖。建立定义染色体轴结构的工作，我们将 确定轴如何与DNA结合粘着素复合物的活性相互作用，以及如何 轴募集并控制重组蛋白以驱动同胞间交叉的形成。接下来，我们 正在追求协作项目，以了解序列和特定于结构的RNA的结构基础 在两个情况下的识别。使用Gene Yeo（UCSD），我们正在开发新一代的可编程 序列特异性RNA结合蛋白与靶向和降解疾病相关的mRNA的蛋白质多种疾病中的mRNA 从癌症到神经变性。使用Matt Daugherty（UCSD），我们正在确定IFIT蛋白如何 哺乳动物先天免疫系统合作，专门识别病毒RNA并抑制其翻译。 最后，我的实验室已经开始了一项新的努力，旨在确定新颖的分子机制 规范基因组维护机器已经适应新角色的细菌防御系统。在 我们在这一领域的第一项工作，我们发现凝蛋白/粘蛋白样MKSBEFG系统保护其 通过特异性识别和切割闭合圆形DNA，细菌宿主从质粒转化中转化。 我对分子机的着迷，尤其是那些在面对基因组完整性的机器 持续的内部和外部攻击。我的研究计划旨在了解分子基础 在各种情况下的基因组维持以及探索蛋白质如何负责基因组的蛋白质 维护在整个进化过程中都适应了新角色。