Nature discovered a new CRISPR gene scissors in two articles in the same period

Like humans, bacteria and archaea are attacked
by viruses.
These microbes have developed their own immune defense strategies to fight pathogens
.
Bacterial defenses, such as the CRISPR-Cas system, have different proteins and functions that help bacteria protect themselves from foreign invaders
.
This defense is based on a common mechanism: CRISPR ribonucleic acid (crRNA), which acts as "guide RNA," helps detect regions of the foreign genome, such as the DNA of viruses, for targeted cleavage
.
CRISPR-associated nucleases (Cas) guided by crRNA can cut their targets like scissors: a natural strategy
that humans utilize in many technologies.

Chase Beisel said: "Considering that different nucleases have been well translated into new and improved technologies, any discovery in this area could bring new benefits
to society.
" Beisel co-sponsored current research
on a specific CRISPR-Cas system with Matthew Begemann of Benson Hill, Missouri, and Ryan Jackson of Utah State University.
The findings were published today in the journal Nature, while another team led by Ryan Jackson and David Taylor of the University of Texas conducted a detailed structural analysis
.

Unlike other known CRISPR nucleases

"We are exploring the CRISPR nuclease that originally came together with Cas12a, which protects bacteria
by recognizing and cutting invasive DNA.
Once we found more, we realized they were different enough from Cas12a to be studied more deeply," said
Oleg Dmytrenko, lead author of the study.
"This exploration led us to discover that these nucleases, which we call Cas12a2, are not only very different from Cas12a, but also from any other known CRISPR nuclease
.
"

The most critical difference is the mechanism
of defensive action.
When Cas12a2 recognizes invasive RNA, nucleases cleave it, but can also destroy other RNAs and DNA within the cell, impairing its growth and limiting the spread
of infection.
"In general, this defense strategy to stop infection has been found in bacteria," said Oleg Dmytrenko, a postdoctoral fellow at HIRI
.
Some other CRISPR-Cas systems work
this way.
However, CRISPR-based defense mechanisms rely on individual nucleases to recognize invaders and degrade cellular DNA and RNA, which has not been observed
before.
”

detail

The protein sequence and structure of Cas12a2 distinguish this nuclease from Cas12a
.
Cas12a2 is activated by a protospacer flanking sequence (PFS) to recognize target RNA that complements the guide RNA
.
Targeted RNA triggers side-stranded nucleic acid cleavage, which degrades RNA, single-stranded DNA, and double-stranded DNA
.
This activity causes cells to stagnate, possibly by destroying DNA and RNA in the cells, thereby impairing growth
.
Cas12a2 can be used for molecular diagnostics and direct detection of RNA biomarkers, which has been proven
by principle.

Devastating rifts

In another team's further structural analysis of nucleases (concurrent in another Nature article), Cas12a2 underwent significant structural changes
after binding to RNA targets at different stages of the immune response.
This, in turn, causes an exposed crack in the nuclease, which can smash any nucleic acid it encounters—be it RNA, single-stranded DNA, or double-stranded DNA
.
The study also found ways to mutate Cas12a2 to alter the nucleic acids
that nucleases degrade after recognizing their RNA targets.
These details open up potentially wide range of technical applications
for the future.

Dmytrenko O, Neumann GC, Hallmark T, Keiser DJ, Crowley VM, Vialetto E, Mougiakos I, Wandera KG, Domgaard H, Weber J, Gaudin T, Metcalf J, Gray BN, Begemann MB, Jackson RN, Beisel CL (2023).
Cas12a2 elicits abortive infection via RNA-triggered destruction of dsDNA.
 Nature, DOI: 10.
1038/s41586-022-05559-3,

Bravo JPK, Hallmark T, Naegle B, Beisel CL, Jackson RN, Taylor DW (2023).
Large-scale structural rearrangements nleash indiscriminate nuclease activity by CRISPR-Cas12a2.
 Nature, DOI: 10.
1038/s41586-022-05560-w