{"title":"Taming AID mutator activity in somatic hypermutation","authors":"Yining Qin , Fei-Long Meng","doi":"10.1016/j.tibs.2024.03.011","DOIUrl":null,"url":null,"abstract":"<div><p>Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) by introducing base substitutions into antibody genes, a process enabling antibody affinity maturation in immune response. How a mutator is tamed to precisely and safely generate programmed DNA lesions in a physiological process remains unsettled, as its dysregulation drives lymphomagenesis. Recent research has revealed several hidden features of AID-initiated mutagenesis: preferential activity on flexible DNA substrates, restrained activity within chromatin loop domains, unique DNA repair factors to differentially decode AID-caused lesions, and diverse consequences of aberrant deamination. Here, we depict the multifaceted regulation of AID activity with a focus on emerging concepts/factors and discuss their implications for the design of base editors (BEs) that install somatic mutations to correct deleterious genomic variants.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 7","pages":"Pages 622-632"},"PeriodicalIF":11.6000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Trends in Biochemical Sciences","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S096800042400077X","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) by introducing base substitutions into antibody genes, a process enabling antibody affinity maturation in immune response. How a mutator is tamed to precisely and safely generate programmed DNA lesions in a physiological process remains unsettled, as its dysregulation drives lymphomagenesis. Recent research has revealed several hidden features of AID-initiated mutagenesis: preferential activity on flexible DNA substrates, restrained activity within chromatin loop domains, unique DNA repair factors to differentially decode AID-caused lesions, and diverse consequences of aberrant deamination. Here, we depict the multifaceted regulation of AID activity with a focus on emerging concepts/factors and discuss their implications for the design of base editors (BEs) that install somatic mutations to correct deleterious genomic variants.
活化诱导胞苷脱氨酶（AID）通过将碱基置换引入抗体基因启动体细胞超突变（SHM），这一过程使免疫反应中的抗体亲和力成熟。如何驯服突变体，使其在生理过程中精确、安全地产生程序性DNA病变，目前仍是一个悬而未决的问题，因为突变体的失调会导致淋巴瘤的发生。最近的研究揭示了 AID 引发诱变的几个隐藏特征：在柔性 DNA 底物上的优先活性、染色质环状结构域内的受限活性、独特的 DNA 修复因子对 AID 引起的病变进行不同的解码，以及异常脱氨的各种后果。在这里，我们描绘了 AID 活性的多方面调控，重点是新出现的概念/因素，并讨论了它们对设计碱基编辑器（BE）的影响，碱基编辑器可以安装体细胞突变来纠正有害的基因组变异。
期刊介绍：
For over 40 years, Trends in Biochemical Sciences (TIBS) has been a leading publication keeping readers informed about recent advances in all areas of biochemistry and molecular biology. Through monthly, peer-reviewed issues, TIBS covers a wide range of topics, from traditional subjects like protein structure and function to emerging areas in signaling and metabolism. Articles are curated by the Editor and authored by top researchers in their fields, with a focus on moving beyond simple literature summaries to providing novel insights and perspectives. Each issue primarily features concise and timely Reviews and Opinions, supplemented by shorter articles including Spotlights, Forums, and Technology of the Month, as well as impactful pieces like Science & Society and Scientific Life articles.
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