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For the first time, scientists captured high-resolution, three-dimensional images of an enzyme precisely cutting DNA strands.
The images – captured with the help of a technique called cryogenic electron microscopy or cryo-EM – reveal new information about the functioning of a gene editing tool called CRISPR-Cas9, this could help researchers develop more efficient versions to modify the targeted genes.
The results – published today in Nature Structural and Molecular Biology – the promise of future treatment and prevention of a series of human diseases caused by mutations in DNA, cancer to cystic fibrosis and Huntington's disease.
"It's exciting to be able to see at such a detailed level how Cas9 actually works to cut and edit strands of DNA," said University of British Columbia researcher Sriram Subramaniam. who led the studies on cryo-EM. "These images provide us with valuable information to improve the efficiency of the gene modification process so that we can hope to more quickly and accurately correct mutations of DNA causing disease in the future. "
CRISPR, abbreviation of CRISPR-Cas9, is a gene editing tool in which the Cas9 enzyme acts as a molecular scissors pair, capable of cutting DNA strands. Once the enzyme has cut DNA to specific sites, insertions and modifications can be made, thus altering the DNA sequence.
To better understand the sequence of events involved in the process, Subramaniam and his colleagues used cryo-EM technology to image the Cas9 enzyme at work. The images provide an unprecedented insight into the stepwise molecular movements that occur during the clipping of DNA by Cas9, including a snapshot of cut DNA still attached to the enzyme immediately before the release.
"One of the biggest obstacles to developing better gene editing tools with Cas9 is the fact that we did not have any image of it actually cutting DNA," said author Miljan Simonovic. Principal of the study, researcher at the University of Illinois. "But now we have a much clearer picture, and we even see how the main areas of the enzyme evolve during the reaction, which could be an important target for the modification."
The Subramaniam laboratory was the first to perform atomic resolution imaging of protein and protein-related drug molecules using cryo-EM. In recent years, they have been the first to use cryo-EM to visualize various proteins, including metabolic enzymes, brain receptors, and DNA-protein complexes.
The study was funded by funds from the US National Cancer Institute, grants from the National Institutes of Health, the UIC Center for Clinical and Translational Sciences, and a Canada Excellence Research Chair position. in Subramaniam.
As Canada's Chair in Research Excellence in the Design of Precision Anticancer Medicine, Subramaniam is leading a laboratory for transformative discoveries in cancer, neuroscience and infectious diseases. Xing Zhu, the first author of the study, and co-author, Sagar Chittori, are members of UBC's Subramaniam Lab.
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Material provided by University of British Columbia. Note: Content can be changed for style and length.
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