Communications biologyMar 11, 2026

How changes to AsCas12a improve its activity

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 16, 2026

Abstract

An engineered variant of Cas12a achieves high potency while maintaining higher intrinsic specificity compared to Cas9.

Cas12a generally exhibits greater specificity but lower potency in DNA cleavage than Cas9.
Recent enhancements in protein engineering aim to improve both the specificity and effectiveness of Cas12a.
The engineered AsCas12a variant showed faster R-loop formation due to reduced protein-DNA interactions.
Enhanced cleavage activity was linked to the structural and mechanistic features of the modified AsCas12a.

Simplified

CRISPR-associated proteins (Cas) are central to gene editing, forming nuclease complexes with guide RNA to enable precise genome modification. Among numerous Cas variants, Cas9 and Cas12a are the most extensively studied. While much is known about the genomic substrates for these enzymes, less is known about the determinants of the DNA cleavage activity. Wild-type Cas12a exhibits higher intrinsic specificity than Cas9, minimizing off-target activity, but lower overall potency. Recent protein engineering has sought to improve both parameters. Here, we shed light on the structural and mechanistic basis by which an engineered AsCas12a variant achieves high potency while retaining its hallmark specificity. We show that reduced protein-DNA interactions facilitate more rapid R-loop formation, thereby enhancing cleavage activity. These results provide mechanistic insight into Cas12a function and highlight strategies for designing genome-editing nucleases with optimal balance between efficiency and specificity.

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Competing interests

Competing interests: L.J-F., J.-N.L., and B.C. declare the following competing interests: current or former employees and shareholders at Editas Medicine, Inc. C.L. and S.W. declare the following competing interests: shareholders at Editas Medicine, Inc. A.O., A.D., A.W., and S.K. declare the following competing interests: current or former employees of Schrödinger and were contracted by Editas Medicine to support crystallographic experiments.

PubMed

How changes to AsCas12a improve its activity

Abstract

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Related papers

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