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Looking under the Bonnet of Molecular Machines on Genes
Model for how the helicase domain of a Type I restriction enzyme acts as a dsDNA translocase using motor contacts to the 3´-5´ strand and processivity contacts to the 5´-3´ strand.
We are interested in how proteins act as nanoscale machines and motors to modify and manipulate DNA. Such processes are central to genome biology, including in DNA replication, recombination and repair. We use a combination of biochemical, biophysical and single molecule techniques to follow these processes in real time and to reveal complex molecular events. Some of our current projects include:
- The arms race between bacteria and bacteriophages. The threat of viral infection has led bacteria to evolve an extensive armoury of Restriction-Modification (RM) systems. Genome wide analysis reveals extensive mosaicity, with diverse molecular machines being employed by even closely related species. In collaboration with Ralf Seidel (Dresden University of Technology) we have been using the RM enzymes as a rich source of simple and tractable systems to study DNA helicase biology. In collaboration with Virginjus Siksnys (Institute of Biotechnology, Vilnius), we are also examining RNA-guided antiviral immunity using CRISPR systems.
- Regulation of DNA architecture during replication initiation. To efficiently copy a genome requires careful control of replication initiation. In bacteria, this requires the assembly of an extensive nucleoprotein complex that causes DNA unwinding and which facilitates the loading of the replicative helicases. Somewhat surprisingly, the exact architecture of this complex is unclear and little is know about its dynamics. In collaboration with Panos Soultanas (University of Nottingham) we are using single molecule techniques to help understand this assembly process.
- Mitochondrial genome maintenance. In collaboration with Nigel Savery, we are starting to study the proteins that help maintain the mitochondrial genome. We are interested both in architectural elements that package the DNA and in transcriptional and replicative elements that allow the genome to be copied.
Fiona Diffin, Kara van Aelst, Ben Tan, Júlia Tóth
Szczelkun MD*,, Tikhomirova M*, Sinkunas T, Gasiunas G, Karvelis T, Pschera P, Siksnys V and Seidel R (2014) Direct observation of R-loop formation by single RNA-guided Cas9 and Cascade effector complexes, Proc. Natl. Acad. Sci. (USA), 111, 9798–9803. *joint authors
[Commentary - Spies M (2014) Fulfilling the dream of a perfect genome editing tool, Proc. Natl. Acad. Sci. (USA), 111, 10029-30]
Butterer A, Pernstitch C, Smith RM, Sobott F, Szczelkun MD and Tóth J (2014) Type III restriction endonucleases are heterotrimeric: comprising one helicase-nuclease subunit and a dimeric methyltransferase that binds only one specific DNA, Nucleic Acids Res., 42, 5139-50.
Schwarz FW, Tóth J, van Aelst K, Cui G, Clausing S, Szczelkun MD*, Seidel R.* (2013) The helicase-like domains of type III restriction enzymes trigger long-range diffusion along DNA. Science. 340: 353-356. *joint senior/communicating authors
Szczelkun MD. (2013) Roles for Helicases as ATP-Dependent Molecular Switches. Advances in Experimental Medicine and Biology. 767: 225-244.
View all publications listed on the University of Bristol's publication database