A chemically controlled Cas9 switch enables temporal modulation of diverse effectors

Cindy T. Wei, Nicholas A. Popp, Omri Peleg, Rachel L. Powell, Elhanan Borenstein, Dustin J. Maly*, Douglas M. Fowler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


CRISPR–Cas9 has yielded a plethora of effectors, including targeted transcriptional activators, base editors and prime editors. Current approaches for inducibly modulating Cas9 activity lack temporal precision and require extensive screening and optimization. We describe a versatile, chemically controlled and rapidly activated single-component DNA-binding Cas9 switch, ciCas9, which we use to confer temporal control over seven Cas9 effectors, including two cytidine base editors, two adenine base editors, a dual base editor, a prime editor and a transcriptional activator. Using these temporally controlled effectors, we analyze base editing kinetics, showing that editing occurs within hours and that rapid early editing of nucleotides predicts eventual editing magnitude. We also reveal that editing at preferred nucleotides within target sites increases the frequency of bystander edits. Thus, the ciCas9 switch offers a simple, versatile approach to generating chemically controlled Cas9 effectors, informing future effector engineering and enabling precise temporal effector control for kinetic studies. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)981-991
Number of pages11
JournalNature Chemical Biology
Issue number8
StatePublished - Aug 2023


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