LINE-1 Retrotransposons & Other Selfish Elements
Our group is interested in repetitive genetic elements called retrotransposons, a major component of all eukaryotic genomes. We study their mechanism of movement (retrotransposition) and how they interact with host cells/organisms. Most of our work is centered on human L1 (LINE-1) elements, constituting greater than 20 percent of our genome. We tackle the study of LINE-1 activity and its regulation from several angles—genetic, molecular, biochemical, systems/bioinformatics and synthetic approaches. These comparative studies help define core mechanisms of retrotransposon regulation and modes of action, providing a wide view of their physiology and relevance to normal and disease states and aging.
Most recently, we identified the double-stranded break repair and Fanconi anemia pathways as strong inhibitors of LINE-1 activity during S/G2 phase. Specifically, the renowned tumor suppressor and DNA repair protein, BRCA1, dictates LINE-1 retrotransposition rates as well as controls ORF2 translation through mRNA regulation. We propose a model in which homologuous recombination factors and LINE-1 machinery compete for DNA strand breaks at the replication fork. These findings also suggest a potential role for LINE-1 in cancer progression in BRCA1 and HR-defective tumors.
Finally, in our newest endeavor we will explore how life transitioned from utilizing RNA as a source of genetic information to the now universally adopted DNA-based genome. As RNA-based cells no longer exist in nature, RNA viruses may represent the last “living” relics of the primordial pre-DNA world. We will create new technologies that will allow us to build essential artificial RNA chromosomes (ARCs) and characterize their stability and performance capacity in yeast and bacterial cells. These new forms of artificial life will help us better understand the RNA to DNA evolutionary transition and possibly shed light onto the origins of life.
Learn more about how BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells.