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Professor Mark Szczelkun

Professor Mark Szczelkun

Professor Mark Szczelkun
B.Sc.(Liv.), Ph.D.(Soton)

Professor of Biochemistry

Area of research

Prokaryotic immunity systems: mechanisms and applications

Office D45
Biomedical Sciences Building,
University Walk, Clifton BS8 1TD
(See a map)

+44 (0) 117 331 2158

Summary

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. We are also adapting the CRISPR/Cas systems for use as gene editing or targeting tools in human mitochondria.

Keywords

  • Nucleases, DNA cleavage mechanisms
  • Restriction-Modification
  • CRISPR
  • Helicases, molecular motors, ATPases
  • Phage avoidance strategies
  • Single molecule microscopy, magnetic and optical tweezers
  • Stopped flow fluorescence
  • Enzymology, kinetics
  • Modelling of kinetic data

Biography

Mark has always had a soft spot for DNA. He studied Biochemistry at the University of Liverpool, followed by training in enzymology with Bernard Connolly (Southampton) and Steve Halford FRS (Bristol), elucidating the roles of short- and long-range DNA interactions by restriction enzymes. Supported by the award of a Wellcome Trust Career Development Fellowship, he established his research group in Bristol in 1998. He was amongst the first in the UK to propose applying a combination of single-molecule and ensemble biochemical techniques to the study of genome rearrangements. Following on from the award of a Wellcome Trust Senior Fellowship in 2002 to continue his work on DNA helicases in bacterial immunity, he took up his academic post in 2007.

Mark has established an international reputation for the study of DNA-protein interactions using biophysical methods, in particular the mechanism of DNA motors, restriction enzymes and CRISPR-Cas. Work within his group is interdisciplinary and has been driven by a number of successful collaborations with physicists, in particular with Ralf Seidel (Leipzig). Mark's successful application of biophysical techniques was recognised in 2004 with the award of the British Biophysical Society Young Investigator Award. His current work is funded by the BBSRC, and the European Research Council. The group is located in the DNA-Protein Interactions Unit, whcih includes other labs interested in genome biology, including: Chambers, Dillingham and Savery. 

  • School Research Director (2018 - present)
  • Professor of Biochemistry, University of Bristol (2010 - present)
  • Reader, University of Bristol (2007-2010)
  • Senior Research Fellow, University of Bristol (2003-2007)
  • Research Fellow, University of Bristol (1998-2003)
  • Research Associate, University of Bristol (1994-1998)
  • Research Assistant University of Southampton (1990-1993)
  • Ph.D. in Biochemistry with Professor Bernard A. Connolly, University of Southampton (1990-1993) 
  • B.Sc. in Biochemistry (upper second class), University of Liverpool (1987-1990) 

Teaching

Macromolecular Structure, Dynamics and Function

Recombinant DNA Technology

Gene Expression and Rearrangement

Cellular Information

Research and Communication Skills

Advanced Options in Biochemistry

Biophysics and Molecular Life Sciences II

Memberships

Organisations

School of Biochemistry

Other sites

School of Biochemistry staff

Recent publications

View complete publications list in the University of Bristol publications system

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