- Ph.D., Massachusetts Institute of Technology, 1990
- B.Sc., McGill University, 1983
Our goal is to understand the molecular mechanisms involved in the movement and regulation of mobile genetic elements. We focus on those mobile elements that have important genomic impacts (e.g., the emergence of antibiotic resistance), have potential in genetic applications, or that represent completely novel mechanisms.
The basic research we are performing is aimed at understanding the various biochemical mechanisms by which discrete pieces of DNA move - or are copied - from one place in the genome to another. In prokaryotes, the process of DNA transposition has a crucial role in the emergence and the spread of antibiotic resistance. DNA transposition has also been hypothesized to be the evolutionary ancestor of Cas1, the spacer acquisition integrase of CRISPR-Cas adaptive immunity systems. Among eukaryotic species, mobile elements have played a large role in remodeling genomes during evolution, and understanding how transposases accomplish their task has implications relevant to those that have become domesticated and now play different roles. My current research involves the characterization of various DNA transposases from the different branches of life.
Applying Our Research
One reason we are interested in eukaryotic transposons is that they can provide valuable experimental tools to manipulate the genomes of eukaryotic cells. For example, they have been used as a way to eliminate genes selectively and to then observe the consequences. Alternatively, the introduction of specific genes is the conceptual foundation of gene therapy approaches to curing diseases. DNA transposition systems in current use in mammalian cells include the resurrected Sleeping Beauty transposon and piggyBac, which are not always ideal for their desired applications. We reasoned that three-dimensional structures of eukaryotic DNA transposases would provide important insights into their mechanisms and regulation.
- The large bat Helitron DNA transposase forms a compact monomeric assembly that buries and protects its covalently bound 5'-transposon end.
- Kosek D, Grabundzija I, Lei H, Bilic I, Wang H, Jin Y, Peaslee GF, Hickman AB, Dyda F.
- Mol Cell (2021 Oct 21) 81:4271-4286.e4. Abstract/Full Text
- Structures of ISCth4 transpososomes reveal the role of asymmetry in copy-out/paste-in DNA transposition.
- Kosek D, Hickman AB, Ghirlando R, He S, Dyda F.
- EMBO J (2021 Jan 4) 40:e105666. Abstract/Full Text
Research in Plain Language
Essentially all organisms harbor enzymes (proteins) that are able to move discrete segments of DNA from one genomic location to another. Their presence provides a way for organisms to respond to environmental changes, and they have been shown to be major drivers of genome evolution. We would like to understand how these proteins work. Our main approach has been to integrate biochemical studies with the determination of three-dimensional structure, either by x-ray crystallography or cryo-electron microscopy, which are methods to visualize these proteins as they interact with DNA.