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DNA is often thought of as a static archive of genetic information. But genomes are subjected to alterations in their structure and content. Much of this plasticity can be attributed to transposons, pieces of DNA that autonomously ‘jump’ between and within genomes. By driving variation and interspecies transfer of genetic data, transposons shape the biology and the evolution of organisms. In bacteria, for instance, CRISPR-Cas genome defence systems are functionally and evolutionarily linked to mobile DNA. But how do transposons move? How do they interact with their hosts? How can we leverage them to artificially modify genomes? To address this, we study the molecular mechanisms of transposon mobilization and use these insights to develop genome engineering tools for research and medicine. Image: Scienseed (www.scienseed.com)
To get a bigger picture of the mechanisms, functions and applications of transposons, we employ an integrative approach, combining structural biology methods with biotechnological approaches. We analyse the macromolecular organization and the mechanistic details underlying DNA mobilization using cryo-electron microscopy and X-ray crystallography together with biochemical and biophysical methods. We investigate the interplay between transposons and host machineries, as CRISPR-Cas systems, and the biotechnological potential of these interactions using cell-based functional assays, protein design and genome engineering experiments. We extend these studies to technologically and therapeutically relevant cells and organisms with collaboration partners to develop transposon-based applications.
Irma studied Biotechnology at the University of Bologna and received a Ph.D. at the European Molecular Biology Laboratory in Heidelberg, where she worked on eukaryotic transposons with Orsolya Barabas. She joined the lab of Martin Jinek at the University of Zurich as a FEBS, EMBO and Branco Weiss postdoctoral fellow to study CRISPR-guided transposons. Irma will start her research lab in May 2023.
CRISPR-associated transposons (CASTs) are the first elements capable of RNA-guided, targeted DNA integration discovered to date. Our structure-function analysis of type V CASTs revealed that an ATPase filament bridges between the CRISPR and transposon machineries. Our results will guide the design of CASTs as programmable, site-specific gene insertion tools (Querques, Schmitz et al., Nature 2021).
In our previous work, we discovered how to put the SB transposase to work using structure-based design and developed a protein-based genome engineering technology, SBProtAct. In collaboration with clinicians, we employed SBProtAct to genetically modify human T cells for CAR-T cell cancer immunotherapies in a more controlled and safer way (Querques, Mades, Zuliani et al., Nature Biotechnol 2019).
Using cryo-EM, we visualized how a CRISPR-Cas system interacts with a transposon, forming an intertwined RNA-dependent machinery and found that the bacterial ribosomal protein S15 takes part in the assembly as an unprecedented, host-encoded player (Schmitz, Querques et al., bioRxiv 2022). Is S15 the last piece to move on the board to win the technological bet with CRISPR-associated transposons?