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Oral: The Function and Mechanism of CRISPR and Its Applications


Revenge of the phage: Anti-CRISPRs strike back.
J. BONDY-DENOMY (1) (1) University of California, San Francisco, U.S.A.

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Bacteria face a constant threat of being infected and killed by viruses called phages. In response, bacteria have developed an adaptive immune system called CRISPR-Cas, which protects cells from phage infection and has recently been repurposed into a revolutionary gene-editing tool. Phages infecting Pseudomonas aeruginosa, however, have evolved a mechanism to interfere with CRISPR-Cas function by producing proteins called “anti-CRISPRs”. We have identified many different anti-CRISPR proteins that are completely distinct from each other and inhibit CRISPR-Cas function through diverse mechanisms. One anti-CRISPR binds to the nuclease protein and inhibits its recruitment, while other anti-CRISPRs bind to the CRISPR-Cas surveillance complex and prevent it from binding to a DNA target. Further, anti-CRISPR proteins have quantifiably different efficiencies, based on whether they target the first step (i.e. DNA binding) or second step (i.e. nuclease recruitment) of CRISPR-Cas function. Anti-CRISPRs that target the first step face a kinetic challenge in battling with CRISPR and are thus inefficient, while an efficient anti-CRISPR targets the second step, but can be driven to inefficiency by upregulating CRISPR-Cas targeting. By studying the outcome of anti-CRISPR – CRISPR interactions, we hope to gain new insight into CRISPR-Cas function and enhance our understanding the natural ecological battle between bacteria and their viruses.