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

基本信息

批准号：
10795245
负责人：
Kevin Daniel Corbett
金额：
$ 3.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10795245
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

项目摘要

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.

项目概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 年创办自己的实验室以来，我在以下领域做出了重大贡献：真核减数分裂中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组装机制。我的实验室还测定了 TRIP13（有丝分裂中 HORMA 结构域信号蛋白的 ATP 酶调节剂）的结构和机制，减数分裂和DNA修复。作为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中，我为研究生教学和建议做出了重大贡献。我也积极参与更广泛的活动科学界，曾参与 NIH 的拨款审查、NSF 的研究生奖学金审查，以及 2019-2020 年曾在 NIH 科学审查中心工作组任职。我的实验室未来五年的工作将集中在一系列多样化但概念相关的领域基因组维护和蛋白质核酸识别方面的问题。我们的主要兴趣是减数分裂专门的两阶段细胞分裂程序，产生单倍体配子，对性至关重要真核生物中的繁殖。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 结合粘连蛋白复合物相互作用并控制其活性，以及如何轴招募并控制重组蛋白以驱动同源间交叉的形成。接下来，我们正在开展合作项目，以了解序列和结构特异性 RNA 的结构基础两种情况下的认可。我们正在与 Gene Yeo (UCSD) 合作开发新一代可编程序列特异性 RNA 结合蛋白可靶向并降解多种疾病中与疾病相关的 mRNA 从癌症到神经退行性疾病。与 Matt Daugherty（加州大学圣地亚哥分校）一起，我们正在确定 IFIT 蛋白如何在哺乳动物先天免疫系统协同特异性识别病毒 RNA 并抑制其翻译。最后，我的实验室开始了一项新的努力，旨在确定新型药物的分子机制。细菌防御系统，其中规范的基因组维护机器已适应新的角色。在我们在该领域的第一项工作，我们发现类似凝缩蛋白/粘连蛋白的 MksBEFG 系统可以保护其通过特异性识别和切割闭环DNA，从质粒转化中分离出细菌宿主。我对分子机器很着迷，特别是那些在面临困难时保持基因组完整性的机器不断的内部和外部攻击。我的研究计划旨在了解不同背景下的基因组维护，以及探索负责基因组的蛋白质如何在整个发展过程中，维护已经适应了新的角色。