Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation

Yanyan Wang; Senxin Zhang; Xinrui Yang; Joyce K Hwang; Chuanzong Zhan; Chaoyang Lian; Chong Wang; Tuantuan Gui; Binbin Wang; Xia Xie; Pengfei Dai; Lu Zhang; Ying Tian; Huizhi Zhang; Chong Han; Yanni Cai; Qian Hao; Xiaofei Ye; Xiaojing Liu; Jiaquan Liu; Zhiwei Cao; Shaohui Huang; Jie Song; Qiang Pan-Hammarström; Yaofeng Zhao; Frederick W Alt; Xiaoqi Zheng; Lin-Tai Da; Leng-Siew Yeap; Fei-Long Meng

doi:10.1016/j.cell.2023.03.030

Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation

Cell. 2023 May 11;186(10):2193-2207.e19. doi: 10.1016/j.cell.2023.03.030. Epub 2023 Apr 24.

Authors

Yanyan Wang¹, Senxin Zhang², Xinrui Yang³, Joyce K Hwang⁴, Chuanzong Zhan⁵, Chaoyang Lian⁵, Chong Wang⁴, Tuantuan Gui⁵, Binbin Wang⁵, Xia Xie⁶, Pengfei Dai⁶, Lu Zhang⁷, Ying Tian⁵, Huizhi Zhang⁸, Chong Han⁶, Yanni Cai⁶, Qian Hao⁵, Xiaofei Ye⁹, Xiaojing Liu⁶, Jiaquan Liu⁶, Zhiwei Cao⁷, Shaohui Huang¹⁰, Jie Song¹¹, Qiang Pan-Hammarström¹², Yaofeng Zhao¹³, Frederick W Alt⁴, Xiaoqi Zheng¹⁴, Lin-Tai Da³, Leng-Siew Yeap¹⁵, Fei-Long Meng¹⁶

Affiliations

¹ State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Department of Mathematics, Shanghai Normal University, Shanghai 200234, China.
³ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
⁴ Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁵ Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁶ State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁷ School of Life Sciences, Fudan University, Shanghai 200438, China.
⁸ Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁹ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 141-83 Stockholm, Sweden; Kindstar Global Precision Medicine Institute, Wuhan 430000, China.
¹⁰ Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; School of Biosciences, University of Chinese Academy of Sciences, Beijing 101499, China.
¹¹ Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
¹² Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 141-83 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
¹³ State Key Laboratory of Farm Animal Biotech Breeding, China Agricultural University, Beijing 100193, China.
¹⁴ Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁵ Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: yeaplengsiew@shsmu.edu.cn.
¹⁶ State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Huashen Institute of Microbes and Infections, Shanghai 200052, China. Electronic address: feilong.meng@sibcb.ac.cn.

PMID: 37098343
DOI: 10.1016/j.cell.2023.03.030

Abstract

Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma.

Keywords: AID; affinity maturation; complementarity-determining region; deaminase; somatic hypermutation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / genetics
Complementarity Determining Regions / genetics
Cytidine Deaminase* / genetics
Cytidine Deaminase* / metabolism
DNA / genetics
DNA, Single-Stranded
Evolution, Molecular
Mice
Mutation
Nucleotide Motifs
Somatic Hypermutation, Immunoglobulin*

Substances

Antibodies
Cytidine Deaminase
DNA
DNA, Single-Stranded
Complementarity Determining Regions