近日，中国科学院分子细胞科学卓越创新中心孟飞龙等研究人员合作发现， 抗体编码序列中的中尺度DNA特征促进体细胞的超突变。该研究于2023年4月24日在线发表于国际一流学术期刊《细胞》。
研究人员表示，体细胞超突变（SHM）由激活诱导的胞苷脱氨酶（AID）启动，在抗体编码序列中产生突变，从而实现亲和力成熟。为什么这些突变本质上集中在三个不连续的互补性决定区（CDR），仍然是个谜。
研究人员发现易感性诱变取决于由AID脱氨酶模体周围的中尺度序列决定的单链（ss）DNA底物灵活性。含有灵活的嘧啶-嘧啶碱基的中尺度DNA序列与AID带正电的表面斑块有效结合，导致优先的脱氨活性。CDR的高突变性在体外脱氨酶试验中是可以模仿的，并且在使用SHM作为主要的多样化策略的物种中是演化保守的。研究人员证明，中尺度的序列改变调整了小鼠体内的突变性，并促进了小鼠中一个原本冷的区域的突变。
这些研究结果表明，抗体编码序列在指导超突变方面具有非编码作用，为合成设计人源化动物模型以优化抗体发现铺平了道路，并解释了淋巴瘤中的AID诱变模式。
附：英文原文
Title: Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation
Author: 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-Hammarstrm, Yaofeng Zhao, Frederick W. Alt, Xiaoqi Zheng, Lin-Tai Da, Leng-Siew Yeap, Fei-Long Meng
Issue&Volume: 2023-04-24
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-determiningregions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis dependson the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequencesurrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidinebases bind effectively to the positively charged surface patches of AID, resultingin preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a majordiversification strategy. We demonstrated that mesoscale sequence alterations tunethe in vivo mutability and promote mutations in an otherwise cold region in mice. Our resultsshow a non-coding role of antibody-coding sequence in directing hypermutation, pavingthe way for the synthetic design of humanized animal models for optimal antibody discoveryand explaining the AID mutagenesis pattern in lymphoma.
DOI: 10.1016/j.cell.2023.03.030
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00327-6