The CRISPR journalJul 23, 2026

Creating and Testing RNA-Guided Modular Base Editors Using Staphylococcus aureus Cas9 Variants and New Enzymes

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 24, 2026

Abstract

Base editors using Staphylococcus aureus Cas9 demonstrate high editing efficiency with low off-target activities.

Modular base editors were developed by combining SaCas9 with various vertebrate enzymes.
These editors showed low-to-undetectable off-target activity and minimal unwanted DNA changes.
Editing efficiency varied among different base editors when applied to various genetic locations.
The platform allows for specific optimization based on the sequence being targeted.
The modularity of this base editing system enhances its potential for targeted genetic modifications.

Simplified

Base editing enables precise genome modifications without introducing DNA double-strand breaks. Using Streptococcus pyogenes Cas9 as a prototype, we previously developed a modular base editing platform in which the deaminase is recruited by an RNA aptamer engineered into the gRNA, thereby separating sequence recognition from base modification. Here, we expanded this modular base editor toolbox by engineering Staphylococcus aureus Cas9 (SaCas9) in combination with various vertebrate effectors derived from activation induced cytidine deaminase (AID) and apolipoprotein B mRNA editing enzyme, catalytic subunit 1 (APOBEC1) orthologs, from bat, lizard, human, and rat. Moreover, we adopted the SaCas9 variants with different protospacer adjacent motif requirements. These base editors generally showed high editing efficiency with low on-target indel formation and low-to-undetectable off-target activities. Quantitative and qualitative differences in editing occur among the base editors when applied to diverse loci, allowing sequence-specific optimization. Together, our study demonstrates the effectiveness of the SaCas9 modular base editors, the robustness of the platform's modularity, and its feasibility for convenient screening of target-specific base editors.

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Creating and Testing RNA-Guided Modular Base Editors Using Staphylococcus aureus Cas9 Variants and New Enzymes

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