Adenine base editor engineering reduces editing of bystander cytosines

You Kyeong Jeong; Seok Hoon Lee; Gue Ho Hwang; Sung Ah Hong; Se eun Park; Jin Soo Kim; Jae Sung Woo; Sangsu Bae

doi:10.1038/s41587-021-00943-2

Adenine base editor engineering reduces editing of bystander cytosines

You Kyeong Jeong
, Seok Hoon Lee
, Gue Ho Hwang
, Sung Ah Hong
, Se eun Park
, Jin Soo Kim
, Jae Sung Woo
, Sangsu Bae^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

88 Citations (Scopus)

Abstract

Adenine base editors (ABEs) catalyze specific A-to-G conversions at genomic sites of interest. However, ABEs also induce cytosine deamination at the target site. To reduce the cytosine editing activity, we engineered a commonly used adenosine deaminase, TadA7.10, and found that ABE7.10 with a D108Q mutation in TadA7.10 exhibited tenfold reduced cytosine deamination activity. The D108Q mutation also reduces cytosine deamination activity in two recently developed high-activity versions of ABE, ABE8e and ABE8s, and is compatible with V106W, a mutation that reduces off-target RNA editing. ABE7.10 containing a P48R mutation displayed increased cytosine deamination activity and a substantially reduced adenine editing rate, yielding a TC-specific base editing tool for TC-to-TT or TC-to-TG conversions that broadens the utility of base editors.

Original language	English
Pages (from-to)	1426-1433
Number of pages	8
Journal	Nature Biotechnology
Volume	39
Issue number	11
DOIs	https://doi.org/10.1038/s41587-021-00943-2
Publication status	Published - 2021 Nov

Bibliographical note

Funding Information:
This research was supported by grants from the National Research Foundation of Korea no. 2020M3A9I4036072, no. 2020R1A6A1A06046728, no. 2021R1A2C3012908 and no. 2021M3A9H3015389 to S.B., and no. 2018R1C1B6004447 to J.-S.W.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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title = "Adenine base editor engineering reduces editing of bystander cytosines",

abstract = "Adenine base editors (ABEs) catalyze specific A-to-G conversions at genomic sites of interest. However, ABEs also induce cytosine deamination at the target site. To reduce the cytosine editing activity, we engineered a commonly used adenosine deaminase, TadA7.10, and found that ABE7.10 with a D108Q mutation in TadA7.10 exhibited tenfold reduced cytosine deamination activity. The D108Q mutation also reduces cytosine deamination activity in two recently developed high-activity versions of ABE, ABE8e and ABE8s, and is compatible with V106W, a mutation that reduces off-target RNA editing. ABE7.10 containing a P48R mutation displayed increased cytosine deamination activity and a substantially reduced adenine editing rate, yielding a TC-specific base editing tool for TC-to-TT or TC-to-TG conversions that broadens the utility of base editors.",

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AU - Jeong, You Kyeong

AU - Lee, Seok Hoon

AU - Hwang, Gue Ho

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AU - Kim, Jin Soo

AU - Woo, Jae Sung

AU - Bae, Sangsu

N1 - Funding Information: This research was supported by grants from the National Research Foundation of Korea no. 2020M3A9I4036072, no. 2020R1A6A1A06046728, no. 2021R1A2C3012908 and no. 2021M3A9H3015389 to S.B., and no. 2018R1C1B6004447 to J.-S.W. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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N2 - Adenine base editors (ABEs) catalyze specific A-to-G conversions at genomic sites of interest. However, ABEs also induce cytosine deamination at the target site. To reduce the cytosine editing activity, we engineered a commonly used adenosine deaminase, TadA7.10, and found that ABE7.10 with a D108Q mutation in TadA7.10 exhibited tenfold reduced cytosine deamination activity. The D108Q mutation also reduces cytosine deamination activity in two recently developed high-activity versions of ABE, ABE8e and ABE8s, and is compatible with V106W, a mutation that reduces off-target RNA editing. ABE7.10 containing a P48R mutation displayed increased cytosine deamination activity and a substantially reduced adenine editing rate, yielding a TC-specific base editing tool for TC-to-TT or TC-to-TG conversions that broadens the utility of base editors.

AB - Adenine base editors (ABEs) catalyze specific A-to-G conversions at genomic sites of interest. However, ABEs also induce cytosine deamination at the target site. To reduce the cytosine editing activity, we engineered a commonly used adenosine deaminase, TadA7.10, and found that ABE7.10 with a D108Q mutation in TadA7.10 exhibited tenfold reduced cytosine deamination activity. The D108Q mutation also reduces cytosine deamination activity in two recently developed high-activity versions of ABE, ABE8e and ABE8s, and is compatible with V106W, a mutation that reduces off-target RNA editing. ABE7.10 containing a P48R mutation displayed increased cytosine deamination activity and a substantially reduced adenine editing rate, yielding a TC-specific base editing tool for TC-to-TT or TC-to-TG conversions that broadens the utility of base editors.

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Adenine base editor engineering reduces editing of bystander cytosines

Abstract

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