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CRISPR enzyme from groundwater bacteria shows unusual properties

CasX is smaller, bends DNA to facilitate cutting

by Megha Satyanarayana
February 10, 2019 | A version of this story appeared in Volume 97, Issue 6


A model showing the DNA-binding domain and active site of CasX, a new CRISPR enzyme. Unwound DNA is stabilized by the NTSB domain, which hasn't been described before in Cas enzymes in use for gene editing.
Credit: Nature
CasX features a unique domain, NTSB, which seems to stabilize unwound DNA and facilitate cleavage.

CRISPR-CasX—James Bond villain or next gene-editing superspy? Researchers led by Jennifer Doudna of the University of California, Berkeley, have uncovered some unusual features in a new gene-editing enzyme found in a search of bacterial DNA in groundwater. CasX, first described in 2016, is smaller than its more famous cousins, Cas9 and Cas12a. This makes it a potentially better candidate for medicinal use as the field turns to viruses to try to get CRISPR systems into the human body, says coauthor Benjamin Oakes, also of UC Berkeley. In addition, by studying crystal structures of CasX, the team found an unusual domain that they then named the non-target strand binding (NTSB) domain, which seems to stabilize unwound DNA, facilitating double-stranded cuts. And after clipping the first strand of DNA, CasX seems to bend the second strand toward the active site, Oakes says, making the second snip easier (Nature 2019, DOI: 10.1038/s41586-019-0908-x). The team continues to characterize CasX, including its potential to be detected and deactivated by the human immune system. Cas9 and Cas12a come from known human pathogens, and as many people have been exposed to those pathogens, it’s not clear whether their immune systems will react to proteins that come from them. CasX’s groundwater source will hopefully allow it to do its work unseen, Oakes says.


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