抗体编码序列中的介观DNA特征促进体细胞高突变。
Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation.
发表日期：2023 Apr 14
作者：
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
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
起源于激活诱导的胞嘧啶去氨酶(AID)的体细胞高变异(SHM)在抗体编码序列中生成突变，以实现亲和力成熟，为什么这些突变内在地集中于三个不相邻的互补决定区(CDR)仍然是个谜。在这里，我们发现易感性突变依赖于由AID脱氨酶模体周围的介观尺度序列确定的单链(ss) DNA底物的柔性。含有柔性嘧啶-嘧啶碱基的介观尺度DNA序列有效地结合到AID的带有正电荷的表面补丁上，导致优先的脱氨活性。CDR高突变性可在体外脱氨酶测定中模拟，并在使用SHM作为主要多样化策略的物种之间保守演化。我们证明，介观尺度序列改变调节体内易突变性并促进小鼠中本来是冷区的突变。我们的结果展示了抗体编码序列在指导高突变的非编码角色，为人类化动物模型的理想抗体发现提供了合成设计的途径，并解释了淋巴瘤中AID突变模式的原因。版权所有©2023 Elsevier Inc.。保留所有权利。
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.Copyright © 2023 Elsevier Inc. All rights reserved.