Translation-dependent degradation of cas12 mRNA triggered by an anti-CRISPR

Apr 29, 2026Nature

Anti-CRISPR triggers breakdown of cas12 mRNA during its protein production

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Abstract

AcrVA2 triggers selective degradation of cas12a mRNA during its translation.

AcrVA2 binds to key amino acid residues near the Cas12a N-terminus.
This binding leads to the degradation of cas12a mRNA, preventing Cas12a production.
The C-terminal domain of AcrVA2 allows it to associate with ribosomes and polysomes.
This co-sedimentation is necessary for the targeted degradation of mRNA during translation.
Homologs of AcrVA2 are found in diverse mobile genetic elements in bacteria lacking cas12a, suggesting potential for broader gene regulation.

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Bacteria encode diverse defence systems, including CRISPR-Cas, to recognize and cleave the DNA of bacteriophages (phages) and other mobile genetic elements. In response, phages encode anti-CRISPR (Acr) proteins that inhibit CRISPR-Cas activity by blocking DNA binding or cleavage. Here we report an unexpected mechanism by which the anti-CRISPR AcrVA2 inhibits Cas12a biogenesis. AcrVA2 binds conserved and functionally important amino acid residues near the Cas12a N-terminus and triggers selective degradation of cas12a mRNA as it is translated. Additionally, conserved residues in the AcrVA2 C-terminal domain enable co-sedimentation with ribosomes and polysomes, which is required to achieve targeted co-translational mRNA degradation. The AcrVA2 C-terminal domain is broadly conserved in homologs encoded by diverse mobile genetic elements, typically in hosts that lack cas12a, suggesting that these homologues may recognize and downregulate alternative substrates in other bacteria. These findings reveal a novel mechanism for molecular conflict and gene regulation in bacteria. 1 2