ArticleNucleic acids research2024
Dimerization of the deaminase domain and locking interactions with Cas9 boost base editing efficiency in ABE8e.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Translating base editors: a decade of progress from the bench to the clinic.Nature reviews. Drug discovery · 2026Review
- Transposon end recognition and pairing by I-F3 CRISPR-associated transposase.Science advances · 2026Article
- Optimizations of Cas12a- and Cas12i-based adenine base editors for efficient precision editing in the plant genome.Journal of integrative plant biology · 2026Article
- Mutagenesis and free energy calculations to optimize the ProRgpB inhibitor loop and identify variants with higher affinity forRSC advances · 2026Article
- Molecular mechanisms and biotechnology applications of CRISPR-Cas12a.Nature reviews. Molecular cell biology · 2026Review
- Prime Editing, CRISPR-Cas9, and NanoCas Genome Editing for Cancer Treatment.Molecular biotechnology · 2026Review
- Precise, minimally evolved adenine base editors generated through mutation reversion analysis.Nature biotechnology · 2026Article
- A combinatorial synthetic strategy for developing genome-editing protein-delivery agents targeting mouse retina.Nature communications · 2026Article
- Adenine base editor correction of pathogenic variations associated with inherited retinal dystrophy in patient iPSC and retinal organoids.Molecular therapy. Nucleic acids · 2025Article
- Design Rules for Expanding PAM Compatibility in CRISPR-Cas9 from the VQR, VRER and EQR variants.bioRxiv : the preprint server for biology · 2025Article
- A Cryptic Binding Pocket Regulates the Metal-Dependent Activity of Cas9.bioRxiv : the preprint server for biology · 2025Article
- Graph Attention Neural Networks Reveal TnsC Filament Assembly in a CRISPR-Associated Transposon.bioRxiv : the preprint server for biology · 2025Article
- Article
- Unveiling Cas8 dynamics and regulation within a transposon-encoded Cascade-TniQ complex.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Flexibility in PAM Recognition Expands DNA Targeting in xCas9.bioRxiv : the preprint server for biology · 2025Article
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9 authors.
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Abstract
CRISPR-based DNA adenine base editors (ABEs) hold remarkable promises to address human genetic diseases caused by point mutations. ABEs were developed by combining CRISPR-Cas9 with a transfer RNA (tRNA) adenosine deaminase enzyme and through directed evolution, conferring the ability to deaminate DNA. However, the molecular mechanisms driving the efficient DNA deamination in the evolved ABEs remain unresolved. Here, extensive molecular simulations and biochemical experiments reveal the biophysical basis behind the astonishing base editing efficiency of ABE8e, the most efficient ABE to date. We demonstrate that the ABE8e's DNA deaminase domain, TadA8e, forms remarkably stable dimers compared to its tRNA-deaminating progenitor and that the strength of TadA dimerization is crucial for DNA deamination. The TadA8e dimer forms robust interactions involving its R98 and R129 residues, the RuvC domain of Cas9 and the DNA. These locking interactions are exclusive to ABE8e, distinguishing it from its predecessor, ABE7.10, and are indispensable to boost DNA deamination. Additionally, we identify three critical residues that drive the evolution of ABE8e toward improved base editing by balancing the enzyme's activity and stability, reinforcing the TadA8e dimer and improving the ABE8e's functionality. These insights offer new directions to engineer superior ABEs, advancing the design of safer precision genome editing tools.
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