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ACS Chem Biol. 2016 Mar 18;11(3):681-8. doi: 10.1021/acschembio.5b01019. Epub 2016 Feb 9.

Chemical and Biophysical Modulation of Cas9 for Tunable Genome Engineering.

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Department of Molecular and Cell Biology, University of California, Berkeley , Berkeley, California 94720, United States.
Department of Chemistry, Howard Hughes Medical Institute, Innovative Genomics Institute, Center for RNA Systems Biology, University of California, Berkeley , Berkeley, California 94720, United States.
Physical Biosciences Division, Lawrence Berkeley National Laboratory , Berkeley, California 94720, United States.


The application of the CRISPR-Cas9 system for genome engineering has revolutionized the ability to interrogate genomes of mammalian cells. Programming the Cas9 endonuclease to induce DNA breaks at specified sites is achieved by simply modifying the sequence of its cognate guide RNA. Although Cas9-mediated genome editing has been shown to be highly specific, cleavage events at off-target sites have also been reported. Minimizing, and eventually abolishing, unwanted off-target cleavage remains a major goal of the CRISPR-Cas9 technology before its implementation for therapeutic use. Recent efforts have turned to chemical biology and biophysical approaches to engineer inducible genome editing systems for controlling Cas9 activity at the transcriptional and protein levels. Here, we review recent advancements to modulate Cas9-mediated genome editing by engineering split-Cas9 constructs, inteins, small molecules, protein-based dimerizing domains, and light-inducible systems.

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