The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage
Open accessAbstract
The spontaneous deamination of cytosine is a major source of transitions from C•G to T•A base pairs, which account for half of known pathogenic point mutations in humans. The ability to efficiently convert targeted A•T base pairs to G•C could therefore advance the study and treatment of genetic diseases. The deamination of adenine yields inosine, which is treated as guanine by polymerases, but no enzymes are known to deaminate adenine in DNA. Here we describe adenine base editors (ABEs) that mediate the conversion of A•T to G•C in genomic DNA. We evolved a transfer RNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR-Cas9 mutant. Extensive directed evolution and protein engineering resulted in seventh-generation ABEs that convert targeted A•T base pairs efficiently to G•C (approximately 50% efficiency in human cells) with high product purity (typically at least 99.9%) and low rates of indels (typically no more than 0.1%). ABEs introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than a current Cas9 nuclease-based method, and can install disease-correcting or disease-suppressing mutations in human cells. Together with previous base editors, ABEs enable the direct, programmable introduction of all four transition mutations without double-stranded DNA cleavage.
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In the citing paper
“Using a seventh-generation evolved transfer RNA adenosine deaminase attached to dCas9, researchers demonstrated conversion of A*T base pairs to G*C base pairs in a targeted fashion at efficiencies of around 50% with few undesired mutations in human cells.”
From Delivering CRISPR: a review of the challenges and approaches (2018) · cites this paper as Gaudelli et al., 2017
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Adenine base editor (ABE), first described in 2017, generally does not induce DSBs (<1%) and is therefore a favorable alternative to Cas9 for single and multiplex gene knockouts.12,14”
From Adenine base editor for knockout of proteins: A practical guide from design to analysis with updated MultiEditRbatch (2026) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Yet, these mutations occur significantly more often in human disease than transversion mutations (62% transition vs 38% transversion29,63).”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [29]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“CBE converts cytosine to thymine”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as Gaudelli et al., 2017
The cited source says what the claim attributes to it.
In the citing paper
“ABE catalyzes the editing from adenine to guanine”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as Gaudelli et al., 2017
The cited source says what the claim attributes to it.
In the citing paper
“Base editors are one such tool, which couple Cas9 nickases with nucleotide deaminases to achieve single nucleotide conversion without introducing DSBs.”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as Gaudelli et al., 2017
The cited source says what the claim attributes to it.
In the citing paper
“Next-generation CRISPR tools, such as base editors, use enzymes like cytidine or adenine deaminases fused to Cas9 to introduce single nucleotide variants (SNVs) without DSBs.12,13”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Fusing adenine deaminase (an evolved TadA heterodimer) to a nickase-Cas9 creates an adenine base editor (ABE) that mediates A > G base changes via an inosine intermediate29”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [29]
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In the citing paper
“The second study used CRISPR-Cas9-mediated genome editing to remove a mutation in exon 23 in the mdx mouse model of DMD, providing partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle 25,26,49 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [49]
Experimental — accuracy not yet measuredIn the citing paper
“Consistent with the literature1, ABE6.3 resulted in the highest A>G base editing efficiency at position A9 (6.9 ± 2.0%,2 µg ABE6.3) (Supplementary Fig. 1) and editing efficiency was dependent of the ABE enzyme concentration.”
From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [1]
In the citing paper
“Adenine BEs comprise an evolved Escherichia coli TadA (ecTadA*, a tRNA adenosine deaminase evolved to accept DNA substrate) and Cas9 nickase, and mediate A•T to G•C substitutions1.”
From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [1]
In the citing paper
“The ABE editing window occupies positions ~4–9 with the 1st, 5’ nucleotide (nt) of the candidate sgRNA counted as position 1 1.”
From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [1]
In the citing paper
“Point mutations are a frequent cause of genetic disease, with ~50% of disease point mutations being G:C>A:T 1.”
From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [1]
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Citations
Cites
Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage
Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A., & Liu, D. R. (2016) · Nature · doi:10.1038/nature17946 · Cited by 5,437
Self-citationClinVar: public archive of interpretations of clinically relevant variants
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GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases
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Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems
Nishida, K., Arazoe, T., Yachie, N., Banno, S., Kakimoto, M., Tabata, M., Mochizuki, M., Miyabe, A., Araki, M., Hara, K. Y., et al. (2016) · Science · doi:10.1126/science.aaf8729 · Cited by 1,349
Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9
Paquet, D., Kwart, D., Chen, A., Sproul, A., Jacob, S., Teo, S., Olsen, K. M., Gregg, A., Noggle, S., & Tessier-Lavigne, M. (2016) · Nature · doi:10.1038/nature17664 · Cited by 951
Precise base editing in rice, wheat and maize with a Cas9-cytidine deaminase fusion
Zong, Y., Wang, Y., Li, C., Zhang, R., Chen, K., Ran, Y., Qiu, J., Wang, D., & Gao, C. (2017) · Nature Biotechnology · doi:10.1038/nbt.3811 · Cited by 896
Komor, A. C., Zhao, K. T., Packer, M. S., Gaudelli, N. M., Waterbury, A. L., Koblan, L. W., Kim, Y. B., Badran, A. H., & Liu, D. R. (2017) · Science Advances · doi:10.1126/sciadv.aao4774 · Cited by 783
Self-citationKim, Y. B., Komor, A. C., Levy, J. M., Packer, M. S., Zhao, K. T., & Liu, D. R. (2017) · Nature Biotechnology · doi:10.1038/nbt.3803 · Cited by 758
Self-citationA system for the continuous directed evolution of biomolecules
Esvelt, K. M., Carlson, J. C., & Liu, D. R. (2011) · Nature · doi:10.1038/nature09929 · Cited by 694
Self-citationUracil in DNA – occurrence, consequences and repair
Krokan, H. E., Drabløs, F., & Slupphaug, G. (2002) · Oncogene · doi:10.1038/sj.onc.1205996 · Cited by 500
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CRISPR-Combo–mediated orthogonal genome editing and transcriptional activation for plant breeding
Pan, C., & Qi, Y. (2023) · Nature Protocols · doi:10.1038/s41596-023-00823-w · Cited by 41
Smekalova, E. M., Martínez, M. G., Combe, E., Kumar, A., Dejene, S., Leboeuf, D., Chen, C., Dorkin, J. R., Shuang, L. S., Kieft, S., et al. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.102112 · Cited by 41
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Xiong, X., Li, Z., Liang, J., Liu, K., Li, C., & Li, J.-F. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac166 · Cited by 41
Lohia, A., Sahel, D. K., Salman, M., Singh, V., Mariappan, I., Mittal, A., & Chitkara, D. (2022) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2022.02.001 · Cited by 33
Base editing for reprogramming cyanobacterium Synechococcus elongatus
Wang, S.-Y., Li, X., Wang, S.-G., & Xia, P.-F. (2023) · Metabolic Engineering · doi:10.1016/j.ymben.2022.11.005 · Cited by 31
Development of multiplexed orthogonal base editor (MOBE) systems
Cowan, Q. T., Gu, S., Gu, W., Ranzau, B. L., Simonson, T. S., & Komor, A. C. (2025) · Nature Biotechnology · doi:10.1038/s41587-024-02240-0 · Cited by 26
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Genome Editing of Veterinary Relevant Mycoplasmas Using a CRISPR-Cas Base Editor System
Ipoutcha, T., Rideau, F., Gourgues, G., Arfi, Y., Lartigue, C., Blanchard, A., & Sirand-Pugnet, P. (2022) · Applied and Environmental Microbiology · doi:10.1128/aem.00996-22 · Cited by 19
Development and application of prime editing in plants
Tingting, L., Jinpeng, Z., Xi, Y., Kejian, W., Yuchun, R., & Chun, W. (2023) · Rice Science · doi:10.1016/j.rsci.2023.07.005 · Cited by 21
Cytosine base editing in cyanobacteria by repressing archaic Type IV uracil‐DNA glycosylase
Lee, M., Heo, Y. B., & Woo, H. M. (2023) · The Plant Journal · doi:10.1111/tpj.16074 · Cited by 15
Rodent Genetic Models of Ah Receptor Signaling
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“…with the advent of techniques like base editing and prime editing that induce editing without double stranded breaks, further improves the range of mutations and the ease with which these specific mutations may be installed(Komor et al. 2016; Gaudelli et al. 2017; Anzalone et al. 2019).”
BackgroundCelotti, M., Derks, L. L. M., van Es, J., van Boxtel, R., Clevers, H., & Geurts, M. H. (2024) · STAR Protocols · doi:10.1016/j.xpro.2024.103189 · Cited by 17
Development of a base editor for convenient and multiplex genome editing in cyanobacteria
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Gene Augmentation and Editing to Improve TCR Engineered T Cell Therapy against Solid Tumors
Lo Presti, V., Buitenwerf, F., van Til, N. P., & Nierkens, S. (2020) · Vaccines · doi:10.3390/vaccines8040733 · Cited by 14
Current advances in CRISPR-Cas-mediated gene editing and regulation in cyanobacteria
Dong, Z., Chen, L., Wang, Y., Sun, T., & Zhang, W. (2024) · Blue Biotechnology · doi:10.1186/s44315-024-00009-3 · Cited by 16
Got mutation? ‘Base editors’ fix genomes one nucleotide at a time.
Ravindran, S. (2019) · Nature · doi:10.1038/d41586-019-03536-x · Cited by 12
Pulman, J., Botto, C., Malki, H., Ren, D., Oudin, P., De Cian, A., As, M., Izabelle, C., Saubamea, B., Forster, V., et al. (2024) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2024.102349 · Cited by 12
Qi, T., Fu, J., Zhang, W., Cui, W., Xu, X., Yue, J., Wang, Q., & Tian, X. (2020) · Translational Cancer Research · doi:10.21037/tcr-20-2118 · Cited by 10
Chromatin structure and context-dependent sequence features control prime editing efficiency
Kim, S., Yuan, J. B., Woods, W. S., Newton, D. A., Perez-Pinera, P., & Song, J. S. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1222112 · Cited by 12
A Pan-RNase Inhibitor Enabling CRISPR-mRNA Platforms for Engineering of Primary Human Monocytes
Laoharawee, K., Johnson, M. J., Lahr, W. S., Sipe, C. J., Kleinboehl, E., Peterson, J. J., Lonetree, C.-L., Bell, J. B., Slipek, N. J., Crane, A. T., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179749 · Cited by 7
Eaton, E. J., Wick, B. J., Chacón, J. S., Wang, A. J., Kluesner, M., Barnes, J. T., Kar, B., Wang, M., Johnson, M. J., Skeate, J. G., et al. (2026) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2026.102908 · Cited by 2
“12,14 The initial ABE enzyme was comprised of a catalytically dead Streptococcus pyo-genes Cas9 (spCas9) fused to a deaminase domain that facilitates the conversion of adenine (A) to inosine (I) within a defined editing window.”
Omura, S. N., Nakagawa, R., Kajimoto, S., Okazaki, S., Ishiguro, S., Mori, H., Onishi, K., Kashiwakura, Y., Hiramoto, T., Horinaka, K., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71626-2 · Cited by 2
Evolution of prime editing systems: move forward to the treatment of hereditary diseases
Volodina, O. V., Fabrichnikova, A. R., Anuchina, A. A., Mishina, O. S., Lavrov, A. V., & Smirnikhina, S. A. (2025) · Current Gene Therapy · doi:10.2174/0115665232295117240405070809 · Cited by 1
Metadata
- Authors
- Gaudelli, N. M., Komor, A. C., Rees, H. A., Packer, M. S., Badran, A. H., Bryson, D. I., & Liu, D. R.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Liu, David R.
- ORCID
- Venue
- Nature
- Published
- 2017-11-01
- Volume
- 551
- Issue
- 7681
- Pages
- 464-471
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5726555
- OpenAlex
- W2766599608
- Cited by
- 4,184
- References
- 46
- Citations by year
- 2026: 460 · 2025: 501 · 2024: 521 · 2023: 599 · 2022: 557 · 2021: 489 · 2020: 474 · 2019: 332 · 2018: 237 · 2017: 8
- FWCI
- 117.56
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-05-02)
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (RM1HG009490)
- National Institute of General Medical Sciences (T32GM008313, F32GM106621, R35GM118062, F32GM112366)
- National Institute of Biomedical Imaging and Bioengineering (R01EB022376)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- adenine base editors, base editing, cytosine deamination, CRISPR/Cas9, directed evolution, protein engineering, transition mutations, point mutations, single nucleotide polymorphisms
- MeSH terms
- Gene Editing, Adenosine Deaminase, DNA, Humans, Models, Molecular, Genome, Human, Base Pairing, Polymorphism, Single Nucleotide, Cell Line, Tumor, DNA Cleavage, HEK293 Cells, CRISPR-Associated Proteins
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