Evolutionary molecular biology of the interplay between the DNA damage response and innate immunity

点击翻译按钮获取中文摘要

The ability to defend against pathogens and faithfully repair DNA damage are fundamental and evolutionarily ancient properties of single-cell and multicellular organisms. The major aim of my NSERC research program is to uncover the evolutionarily conserved yet complex interplay between innate immune pathways and cellular response to DNA damage. As eukaryotic organisms evolved so did their pathogens, and “innate” systems for sensing foreign biomolecules (including DNA and RNA) began to emerge. For multicellular organisms, this took the form of innate immunity, where intracellular proteins that recognize both foreign as well as damaged “self” DNA turn on gene pathways that lead to inflammation. This inflammation can result in interferon production that is important in fighting viral infections and attracting immune cells to aid wound healing but can also trigger cellular senescence and aging. The details of how these pathways interconnect are only partly understood but recent studies have provided evidence that the basic machinery underlying the detection of damaged DNA and activation of innate immunity is at least 600 million years old. Specifically, proteins called GMP-AMP Synthase (cGAS) and STimulator of Interferon Genes (STING) are chiefly responsible for detecting damaged DNA in the cytoplasm of cells, and STING may have first evolved to respond to pathogens affecting single cell flagellates. In vertebrates, cGAS-STING is responsible for secretion of both interferons and senescence-associated and inflammatory cytokines like IL-6. Keeping cGAS-STING in check are DNA enzymes called exonucleases that can degrade cytoplasmic DNA but can also play roles in DNA repair. By analysing multiple vertebrate genomes, from species including amphibians such as the axolotl, zebrafish and the “living fossil” fish known as the spotted gar, we have traced the evolutionary origins of a novel family of exonucleases that we hypothesize have a role in innate immunity and DNA repair. Using the spotted gar genome as our “Rosetta stone”, and both the axolotl and zebrafish as cell and animal models, we will characterize the cellular functions of these exonucleases in innate immune signaling, DNA damage responses and repair, senescence and wound-healing by combining CRISPR gene editing, zebrafish transgenic models and advanced live-cell imaging techniques. Together, these studies will provide an exceptional opportunity for multi-disciplinary training of graduate and undergraduate trainees, and will foster our long term goal of uncovering the complex interplay between DNA repair and innate immune pathways that underlie pathogen defense, wound-healing and aging.