Research by the Biosciences Department of Durham University and collaborators at the University of Liverpool and the University of Northumbria has discovered a new bacterial defence mechanism which has future biotechnology applications.
Bacteria and the viruses that infect them, (called bacteriophages, or phages) are intertwined in an endless cycle of competition. Similarly to human viruses, phages continuously evolve to escape the immune systems of their hosts. After injecting their genetic material into a bacterial cell, phages subvert their cellular machinery, replicate within and subsequently destroy the cell, releasing their brethren to infect neighbouring bacteria and repeating their parasitic lifestyle.
However, bacteria have many types of defence mechanisms to destroy their would-be invaders. These bacterial defence mechanisms are many and varied but often involve enzymes to precisely slice up the phage’s genetic material after it invades. For example, their CRISPR Cas systems that have revolutionised biotechnology, or their more unknown Bacteriophage Exclusion system (BREX) which uses multiple enzymes to modify phage DNA to stop them from replicating.
The researchers and their collaborators tracked different defence systems in bacterial genetic material and found that the bacterium Escherichia fergusonii used the BREX system alongside a new type of DNA cutting enzyme to defend itself from phages.
97 students completing their BSc or MBiol degrees in Biological Sciences at Durham University contributed to this study by collecting and purifying phages in workshops during their final or penultimate years of study. These phages were then used to test the new defence mechanism after it was inserted into another species of closely related bacteria, Escherichia coli. Subsequently, researchers found that BREX and the new enzyme termed ‘BRxU’ work together to defend against phage infection. They were able to discover that BrxU recognises multiple DNA modifications found in phage genomes, added to evade different bacterial immune system proteins, like BREX, and cleaves the DNA. This system is not perfect, with some phages being able to dodge the tag-team defence of BrxU and BREX systems.
The special aspect of BrxU is its ability to recognise multiple phage DNA sequences with different DNA modifications, which are also used in humans to control gene expression. Gene expression is the system which allows different cells to have different structures and functions through the switching on and off genes to produce proteins specific to various cell types. This allows complex organisms like humans to have specialised cells which carry out distinct functions. Another level of complexity is found in the pattern of gene regulation through chemical modifications of DNA and proteins associated with it: this is called the epigenome. Accordingly, the epigenome also has some role in memory formation, ageing, development and other essential processes. Problems with the epigenome are central to many severe diseases which are incurable or hard to treat such as autoimmune diseases, neurological disorders and some types of cancer.
Therefore, an enzyme which can recognise and cut DNA sequences with these epigenetic markers may allow researchers to develop this bacterial immune system into a new type of biotechnological tool to simplify laboratory techniques for characterising the epigenome of cells. There is still work to be done, as the researchers still need to discover the full scope of modifications and sequences recognised by BrxU and the way it conducts chemical reactions to fulfil its purpose. However, BrxU may have a role in the further understanding of the field of epigenetics.
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