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

Department of Life Sciences

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

51 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

Access to Document

10.1038/s41587-021-00943-2

Cite this

@article{e122190d769b46d583dabc9413ca97c5,

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.",

author = "Jeong, {You Kyeong} and Lee, {Seok Hoon} and Hwang, {Gue Ho} and Hong, {Sung Ah} and Park, {Se eun} and Kim, {Jin Soo} and Woo, {Jae Sung} and Sangsu Bae",

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: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = nov,

doi = "10.1038/s41587-021-00943-2",

language = "English",

volume = "39",

pages = "1426--1433",

journal = "Nature Biotechnology",

issn = "1087-0156",

publisher = "Nature Publishing Group",

number = "11",

}

TY - JOUR

T1 - Adenine base editor engineering reduces editing of bystander cytosines

AU - Jeong, You Kyeong

AU - Lee, Seok Hoon

AU - Hwang, Gue Ho

AU - Hong, Sung Ah

AU - Park, Se eun

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.

PY - 2021/11

Y1 - 2021/11

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.

UR - http://www.scopus.com/inward/record.url?scp=85109254847&partnerID=8YFLogxK

U2 - 10.1038/s41587-021-00943-2

DO - 10.1038/s41587-021-00943-2

M3 - Article

C2 - 34211162

AN - SCOPUS:85109254847

SN - 1087-0156

VL - 39

SP - 1426

EP - 1433

JO - Nature Biotechnology

JF - Nature Biotechnology

IS - 11

ER -

Adenine base editor engineering reduces editing of bystander cytosines

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this