Scientists from Durham University, in collaboration with the University of Liverpool, Northumbria University, and New England Biolabs, plan to exploit newly characterized defense systems in bacteria to compare changes to the human genome.

Undergraduates at Durham University have also been working on this research to demonstrate the complex workings of bacterial innate immunity. Bacteria have evolved a multitude of defense systems to protect themselves bacteriophages. Many of these systems have already been developed into useful biotechnological tools, such as for gene editing, where small changes are made to the target DNA.

The current study (“The phage defence island of a multidrug resistant plasmid uses both BREX and type IV restriction for complementary protection from viruses”) in Nucleic Acids Research.

“Bacteria have evolved a multitude of systems to prevent invasion by bacteriophages and other mobile genetic elements. Comparative genomics suggests that genes encoding bacterial defence mechanisms are often clustered in ‘defence islands’, providing a concerted level of protection against a wider range of attackers. However, there is a comparative paucity of information on functional interplay between multiple defence systems,” write the investigators.

“Here, we have functionally characterised a defence island from a multidrug resistant plasmid of the emerging pathogen Escherichia fergusonii. Using a suite of thirty environmentally-isolated coliphages, we demonstrate multi-layered and robust phage protection provided by a plasmid-encoded defence island that expresses both a type I BREX system and the novel GmrSD-family type IV DNA modification-dependent restriction enzyme, BrxU.

“We present the structure of BrxU to 2.12 Å, the first structure of the GmrSD family of enzymes, and show that BrxU can utilise all common nucleotides and a wide selection of metals to cleave a range of modified DNAs. Additionally, BrxU undergoes a multi-step reaction cycle instigated by an unexpected ATP-dependent shift from an intertwined dimer to monomers.

“This direct evidence that bacterial defence islands can mediate complementary layers of phage protection enhances our understanding of the ever-expanding nature of phage-bacterial interactions.”

Bacteriophage [Tim Blower, PhD, Durham University]

The researchers demonstrated that two defense systems worked in a complementary manner to protect the bacteria from bacteriophages. One system protected the bacteria from bacteriophages that did not have any modifications to their DNA. Some bacteriophages modify their DNA to avoid this first defense system.

A second system, called BrxU, protected the bacteria from those bacteriophages with modified DNA, thereby providing a second layer of defence. The researchers built a detailed 3-D picture of BrxU to better understand how it protects from bacteriophages with modified DNA.

BrxU has the potential to be another useful biotech tool because the same DNA modifications that BrxU recognizes, appear throughout the human genome, and alter in cancer and neurodegenerative diseases.

According to senior author of the study, Tim Blower, PhD, an associate professor and Lister Institute Prize Fellow in Durham University’s department of biosciences, “Being able to recognize modified DNA is crucial, as similar modifications are found throughout the DNA of the human genome. This extra layer of information, the ‘epigenome,’ alters as we grow, and also changes in cases of cancer and neurodegenerative diseases.

“If we can develop BrxU as a biotechnological tool for mapping this epigenome, it will transform our understanding of the adaptive information controlling our growth and disease progression.”

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