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

项目摘要 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有着浓厚的兴趣。 上维护自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。我的实验室还确定了 TRIP13是有丝分裂中HORMA结构域信号蛋白ATP酶调节剂， 减数分裂和DNA修复。作为加州大学圣地亚哥分校生物医学科学的副教授和副主席 研究生课程，我贡献显着研究生教学和咨询。我还积极参与更广泛的 科学界，参与了NIH的拨款审查，NSF的研究生奖学金审查， 曾在2019 - 2020年在NIH科学评论中心任职。 我的实验室在未来五年的工作将集中在一个多样化的，但概念上相关的一套 基因组维护和蛋白质-核酸识别的问题。我们的主要兴趣是减数分裂， 一种特殊的两阶段细胞分裂程序，产生单倍体配子，对有性生殖至关重要。 真核生物的繁殖在我们定义染色体轴结构的基础上，我们将 确定该轴如何与DNA结合粘附素复合物相互作用并控制其活性，以及 轴招募和控制重组蛋白，以驱动同源物间交叉的形成。接下来我们 正在进行合作项目，以了解序列和结构特异性RNA的结构基础 在两种情况下承认。通过Gene Yeo（UCSD），我们正在开发新一代可编程 序列特异性RNA结合蛋白靶向和降解不同疾病中的疾病相关mRNA 从癌症到神经退化与马特Daughter（UCSD），我们正在确定如何IFIT蛋白在 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，我的实验室已经开始了一项新的努力，旨在确定新的分子机制。 细菌防御系统，其中典型的基因组维护机器已经适应了新的角色。在 我们在这一领域的第一项工作，我们已经发现，凝聚素/凝聚素样MksBEFG系统保护其 通过特异性识别和切割闭合环状DNA，从质粒转化中分离细菌宿主。 我对分子机器很着迷，特别是那些在面对生物体时保持基因组完整性的机器。 不断的内部和外部攻击。我的研究项目旨在了解 在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 在整个进化过程中，维护者已经适应了新的角色。

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.