Professor Mark Szczelkun
B.Sc.(Liv.), Ph.D.(Soton)
Expertise
Current positions
Professor of Biochemistry
School of Biochemistry
Contact
Press and media
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Research interests
The research focus of the group is the mechanistic analysis of DNA recognition and cleavage by prokaryotic defence systems such as Restriction-Modification and CRISPR. These enzymes protect bacteria from bacteriophages and thus moderate horizontal gene transfer. In addition, they are also important as the basis of many lab tools for manipulating DNA, such as the emergent genome editing technologies.
We use a dual experimental approach to studying DNA-protein interactions – combining single molecule microscopy with ensemble biochemistry, the latter including millisecond time-resolution rapid-mixing fluorescence spectroscopy, molecular biology and protein chemistry. More recently we have established collaborations to extend our studies to human cell culture.
DNA cleavage mechanisms in Restriction-Modification
We have focussed our research efforts on Restriction-Modification enzymes that use ATP-dependent protein machines to evade virus infection, addressing how these "molecular motors" convert chemical energy into mechanical events that lead to DNA cleavage. We have been able to demonstrate alternative properties of the helicase-like motor domains of these enzymes, including dsDNA translocation or molecular switching. These activities allow the enzymes to interact with sites that are distant along a phage genome. We aim to understand the diversity of these mechanisms, and their potential fitness costs to the bacteria.
The CRISPR/Cas effector nucleases
The Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR) and the CRISPR-associated (cas) genes comprise an adaptive immune system in bacteria and archaea. Silencing of foreign nucleic acids by CRISPR/Cas systems relies on a small CRISPR RNA (crRNA), the latter derived by processing transcribed CRISPR repeat-spacer arrays. We have developed a single molecule assay that allows the crRNA-guided recognition of specific DNA sequences to be followed in real time. Understanding how CRISPR/Cas systems achieve specificity will be particularly important in the manipulation of these proteins as tools for genome surgery, where specificity is paramount.
Projects and supervisions
Research projects
sLoLa:Diverse and multi-layered bacterial genome defences in bacteria: linking molecular mechanisms to bacterial-MGE conflicts in single cells, populations, and communities
Principal Investigator
Managing organisational unit
School of BiochemistryDates
01/01/2023 to 31/12/2027
Visual biochemistry of nucleic acid-protein interactions using a multi-user single molecule optical trapping fluorescence microscope.
Principal Investigator
Managing organisational unit
School of BiochemistryDates
01/08/2022 to 31/07/2023
Visual biochemistry of nucleic acid-protein interactions using a multi-user single molecule optical trapping fluorescence microscope.
Principal Investigator
Managing organisational unit
School of BiochemistryDates
01/08/2022 to 31/07/2023
A mechanistic framework for DNA recognition and cleavage by Type V CRISPR-Cas effector nucleases
Principal Investigator
Managing organisational unit
School of BiochemistryDates
14/02/2019 to 31/07/2022
EPICut - Molecular mechanisms, evolutionary impacts and applications of prokaryotic epigenetic-targeted immune systems
Principal Investigator
Description
Interactions between bacteria and their viruses (bacteriophages) have led to the evolution of a wide range of bacterial mechanisms to resist viral infection. The exploitation of such systems has produced…Managing organisational unit
School of BiochemistryDates
01/08/2018 to 31/07/2023
Thesis supervisions
Publications
Recent publications
02/01/2024Short-range translocation by a restriction enzyme motor triggers diffusion along DNA
Nature Chemical Biology
Multi-layered genome defences in bacteria
Current Opinion in Microbiology
Bacteriostatic antibiotics promote CRISPR-Cas adaptive immunity by enabling increased spacer acquisition
Cell Host & Microbe
CRISPR-Cas12a-mediated DNA clamping triggers target-strand cleavage
Nature Chemical Biology
ENDO-Pore
Nucleic Acids Research