CRISPR/Cas9 genome editing is quickly revolutionizing biomedical research, but the new technology is not yet exact. The technique can inadvertently make excessive or unwanted changes in the genome and create off-target mutations, limiting safety and efficacy in therapeutic applications. Now, researchers at the University of Massachusetts (UMass) Medical School and the University of Toronto have discovered the first known "off-switches" for CRISPR/Cas9 activity, providing much greater control over the edits, according to a new study published online on December 8, 2016 in Cell. The Cell article is titled “Naturally Occurring Off-Switches for CRISPR-Cas9.” Erik J. Sontheimer (photo), Ph.D., Professor in the RNA Therapeutics Institute at UMass Medical School, and Alan Davidson, Ph.D., Professor of Molecular Genetics, and Karen Maxwell, Ph.D., Assistant Professor of Biochemistry, at the University of Toronto, identified three naturally-occurring proteins that inhibit the Cas9 enzyme. These proteins, known as anti-CRISPRs, have the ability to block DNA cleavage by the Cas9 nuclease. "CRISPR/Cas9 is a good thing because it introduces specific chromosome breaks that can be exploited to create genome edits, but because chromosome breakage can be hazardous, it is possible to have too much of a good thing, or to have it go on for too long," Dr. Sontheimer said. "There is a current shortage of reliable ways to turn off Cas9 once it has already been delivered to a cell. If you can trip an off-switch after the correct editing is done, then the problem is relieved. We report the first known natural inhibitors of Cas9 activity." "CRISPR is very powerful, but we have to be able to turn it off," Dr. Davidson said. "This is a very fundamental addition to the toolbox, which should give researchers more confidence to use gene editing."
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