Mechanistic studies of prokaryotic genome defense mechanisms
The constant biological arms race between prokaryotic organisms and invading mobile genetic elements has resulted in the evolution of sophisticated genome defense mechanisms. The genes encoding for immunity commonly reside in genomic clusters known as defense islands that are in the vicinity of other host-defense loci.  Recent studies of defense islands have uncovered ten novel host defense mechanisms whose molecular mechanisms remain elusive at present. The proposed project aims to provide a mechanistic basis for genetic immunity in two novel host defense systems: Druantia and Shedu. These systems contain genes encoding nucleases, ATPases and helicases, which strongly suggests that they provide immunity by directly targeting invading nucleic acids. To unravel the molecular mechanisms that underpin immunity in these systems, I will apply a highly interdisciplinary approach by using biochemical and state-of-the-art structural biology techniques, including high-throughput X-ray crystallography, cryo-EM and crosslink-coupled mass spectrometry. Understanding these mechanisms will provide fundamentally new insights into prokaryotic biology and the evolution of host-virus defense systems. Furthermore, these studies might uncover novel molecular activities that may be exploited for use as genetic engineering tools.