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Anti-CRISPR Proteins

Anti-CRISPR Proteins

Anti-CRISPR proteins, encoded by phages and other mobile genetic elements, interact with CRISPR-Cas systems to inactivate them. While CRISPR-Cas systems have evolved to recognizes and kill viruses, anti-CRISPR proteins have evolved in viruses as a counter-defense. Like CRISPR-Cas, anti-CRISPR proteins have applications in genome editing.

In the evolutionary arms race between phage and bacteria, mutations can allow phages to escape CRISPR-Cas-mediated destruction. However, bacteria are quick to acquire new spacer sequences which allow them to retarget phage mutants. Anti-CRISPR proteins are another defense mechanism for phages to escape destruction from CRISPR-Cas systems.

There are 22 unique families of anti-CRISPR proteins. Some act by disrupting DNA binding and others inhibit the cleavage of target sequences.The first anti-CRISPR proteins were identified in 2013 by a research group lead by Alan R. Davidson at University of Toronto . Anti-CRISPR proteins have been identified in multiple bacteria genera that target type I and type II CRISPR-Cas systems.Anti-CRISPR proteins that target the CRISPR-Cas9 system, commonly used for genome editing were identified in 2016 and 2017 by Davidson’s group and Joseph Bondy-Denomy’s group at University of California, San Francisco. In genome editing for therapeutic uses, anti-CRISPR proteins may provide a valuable “off switch” for better control of Cas9 activity. Anti-CRISPR proteins have been shown to reduce off-target cutting by CRISPR-Cas9 in human cells.

Defense Advanced Research Projects Agency (DARPA) supported two research studies published in Science in 2018 that identified new anti-CRISPR proteins, including one that inhibits CRISPR-Cas12a, which is becoming more popular for genome editing applications. DARPA supported this research because of the potential for anti-CRISPR proteins to be used as a countermeasure against nefarious use of CRISPR.The two research groups are Jennifer Doudna’s at University of California, Berkeley and Bondy-Denomy’s group.Jennifer Doudna previously founded the company Caribou Biosciences which is developing various applications for CRISPR-Cas technology.

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Systematic discovery of natural CRISPR-Cas12a inhibitors

Kyle E. Watters, Christof Fellmann, Hua B. Bai, Shawn M. Ren, Jennifer A. Doudna

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Adding this protein to human cells makes CRISPR-Cas9 more specific

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