CRISPR has been in the news for its revolutionary use in new medicines and its controversial use in embryo editing. That’s because CRISPR enables researchers to make precise cuts in DNA to change an organism’s genetic code with minimal time and effort.  It’s easy to forget that CRISPR was not invented for these purposes, but in fact evolved in bacteria as an immune system to defend against bacteriophages (“phages”), viruses that specialize in infecting bacteria. It is also the case that CRISPR isn’t just one system; it represents a wide array of related defense systems spanning 6 types, and we are continually finding more. Most CRISPR systems cut DNA, but a few target RNA. Recently, a tool developed in the arms race between bacteria and phages was uncovered by two research groups. They found that “jumbo phages” can physically shield their DNA from bacterial CRISPR defense systems. 

Mendoza et al. and Malone et al. showed that the related jumbo phages phiKZ and Serratia, respectively, resisted CRISPR attacks from  the bacteria Pseudomonas aeruginosa. Both of these groups showed that once the phage infected host cells, it did not leave its DNA to float freely throughout the cell but instead shielded it in a protein shell. This shell is structurally similar to the nucleus from our cells but is not made with the same fatty molecules. Amazingly, phages that assembled these nucleus-like compartments were highly resistant to multiple types of CRISPR attacks targeted to their DNA. When the phage’s DNA was chemically extracted from the shell, the same CRISPR systems could easily neutralize it. The jumbo phages were also resistant to a related class of defense proteins called restriction enzymes that can cut viral DNA. Mendoza et al. further tested this by attaching a restriction enzyme to a viral protein to guide it into the shell. Once inside, the enzyme was able to cut the phage DNA and fight off infection. Like in all living things, phage DNA must converted into an RNA intermediate. While the DNA is protected, the RNA must still exit the nucleus to be translated into functional protein. Some CRISPR systems target the RNA intermediate instead of DNA, and these systems were still effective at fighting off infection.

While CRISPR counter-defenses have been previously observed in phages, they generally block only one very specific type of CRISPR. This newly discovered defense system has proven to be far more versatile. The ability to defend against all types of DNA-targeting CRISPR systems shows the richness of mechanisms that have evolved out of the arms race between bacteria and phage. It also shows how much we still have left to discover about CRISPR from naturally occurring bacteria and viruses. They may help us make innovate new ways to use this system for revolutionary new medicines and treatments. 

Managing correspondent: Julian Segert

Original articles:

A bacteriophage nucleus-like compartment shields DNA from CRISPR nucleases Mendoza et al. Nature

 A jumbo phage that forms a nucleus-like structure evades CRISPR–Cas DNA targeting but is vulnerable to type III RNA-based immunity Malone et al. Nature

Press article: The Startling Secret of an Invincible Virus The Atlantic

Image: Wikipedia