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CRISPR has jumped to the forefront of gene editing, with game-changing applications like gene therapy, GMO-free designer crops, and synthetic organisms. It makes precise engineering and control of nearly any genome possible. But CRISPR is not perfect and its continued development relies on understanding and modifying the naturally occurring enzymes.

While countless CRISPR systems have been discovered, CRISPR-Cas9 is the most popular. It is composed of one Cas9 protein and two CRISPR ribonucleic acid (RNA) molecules that guide it to the DNA target for editing. Characterizing the intimate structure-activity relationship between Cas9 and it鈥檚 guide RNAs is a bottleneck for certain therapeutic applications.

The Masad Damha group, in collaboration with Keith Gagnon鈥檚 group at the Southern Illinois University School of Medicine, recently undertook an extensive investigation of the CRISPR-Cas9 structure-activity relationship using a wide array of chemical modifications to the CRISPR RNA. Biochemical rules governing the unique protein-RNA partnership were uncovered, including the 鈥渨hat,鈥� 鈥渨hy鈥� and 鈥渨here鈥� of chemical modification compatibility. These results establish guidelines for chemical modification for a broad set of applications and were recently published in Nucleic Acids Research.