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

点击翻译按钮获取中文摘要

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.