New CRISPR protein discovered that destroys infected cells

A newly described CRISPR-associated protein can kill infected cells by cutting all types of DNA and RNA.

Scientists in the USA and Germany have collaborated to describe the structure and function of a novel bacterial immune protein, Cas12a2 which works differently than any other seen so far.

'With this new system… we're seeing a structure and function unlike anything that's been observed in CRISPR systems to date,' said Dr Ryan Jackson from Utah State University, corresponding author of two papers on the findings, both published in Nature here and here.

CRISPR and its associated proteins form part of the bacterial immune system against viruses and have been harnessed by scientists for genome editing technologies. CRISPR refers to the guide RNA molecules that recognise target DNA sequences, and the Cas proteins perform an action once the target has been bound. Most famously Cas9 is often described as 'a pair of scissors' that cuts through both strands of DNA at the target site.

Cas12a2 protein is unique in its ability to cut through any sequence of single-stranded RNA, and single- or double-stranded DNA, leading to comparisons with a Swiss army knife rather than scissors.

Using a technique called cryo-electron microscopy, the team was able to observe the Cas12a2 protein physically alter its shape upon binding to its target, changing from an inhibited to an activated structure. It is this active structure that gives Cas12a2 the ability to bind to any genetic material and cut in random locations:

'Cas12a2 basically grabs the two ends of the DNA double helix and bends it really tightly. And so, the helix in the middle pops open, and then this allows this active site to destroy the bits of DNA that become single-stranded,' said co-first author Dr Jack Bravo from the University of Texas Austin. 'This is what makes Cas12a2 different from all the other DNA-targeting systems.'

However, once activated Cas12a2 does not discriminate between viral or host genetic material and can therefore induce death of the infected cell. This is known as an abortive infection system, which protects the whole bacterial colony, as it prevents the spread of the virus.

If Cas12a2 were to be used in humans to treat conditions such as cancer, Cas12a2 would have to be programmed to only kill cancerous cells and avoid healthy ones.

Dr Jackson said: 'If Cas12a2 could be harnessed to identify, target, and destroy cells at the genetic level, the potential therapeutic applications are significant… We're just scratching the surface, but we believe Cas12a2 could lead to improved and additional CRISPR technologies that will greatly benefit society.'