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Anti-CRISPR-mediated control of gene editing and synthetic circuits in eukaryotic cells

Muneaki Nakamura,P. Srinivasan,Michael G Chavez,Matthew A. Carter,Antonia Dominguez,Marie La Russa,Matthew B. Lau,Timothy R. Abbott,Xiaoshu Xu,Dehua Zhao,Yuchen Gao,Nathan H. Kipniss,C. Smolke,Joseph Bondy-Denomy,Lei S. Qi

Published 2019 in Nature Communications

ABSTRACT

Repurposed CRISPR-Cas molecules provide a useful tool set for broad applications of genomic editing and regulation of gene expression in prokaryotes and eukaryotes. Recent discovery of phage-derived proteins, anti-CRISPRs, which serve to abrogate natural CRISPR anti-phage activity, potentially expands the ability to build synthetic CRISPR-mediated circuits. Here, we characterize a panel of anti-CRISPR molecules for expanded applications to counteract CRISPR-mediated gene activation and repression of reporter and endogenous genes in various cell types. We demonstrate that cells pre-engineered with anti-CRISPR molecules become resistant to gene editing, thus providing a means to generate “write-protected” cells that prevent future gene editing. We further show that anti-CRISPRs can be used to control CRISPR-based gene regulation circuits, including implementation of a pulse generator circuit in mammalian cells. Our work suggests that anti-CRISPR proteins should serve as widely applicable tools for synthetic systems regulating the behavior of eukaryotic cells.Anti-CRISPR proteins derived from phage can abrogate CRISPR activity. The authors repurpose these molecules for demonstrating genomic write-protection and pre-programmed gene expression circuits.

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