抗体体细胞超突变过程中 DNA 损伤和修复的分子机制。

IF 8 2区 生物学 Q1 BIOLOGY Science China Life Sciences Pub Date : 2024-11-01 Epub Date: 2024-07-23 DOI:10.1007/s11427-024-2615-1
Qian Hao, Jinfeng Li, Leng-Siew Yeap
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摘要

抗体多样化对有效的免疫反应至关重要,而体细胞超突变(SHM)是这一适应过程中的关键分子过程。活化诱导胞苷脱氨酶(AID)通过诱导 DNA 病变启动体细胞超突变,最终转化为点突变以及小的插入和缺失(indels)。这些突变结果有助于抗体亲和力的成熟。产生点突变和嵌合突变的机制涉及碱基切除修复(BER)和错配修复(MMR)途径,这两种途径协调良好,既能保持基因组的完整性,又能发生有益的突变。在这方面,转座子合成(TLS)聚合酶通过绕过 DNA 病变,促进了抗体基因突变结果的多样性。本综述总结了我们目前对在 SHM 过程中产生点突变和嵌合体的不同分子机制的理解。了解这些机制对于阐明广谱中和抗体(bnAbs)和自身抗体的发展至关重要,对疫苗设计和治疗也有影响。
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Molecular mechanisms of DNA lesion and repair during antibody somatic hypermutation.

Antibody diversification is essential for an effective immune response, with somatic hypermutation (SHM) serving as a key molecular process in this adaptation. Activation-induced cytidine deaminase (AID) initiates SHM by inducing DNA lesions, which are ultimately resolved into point mutations, as well as small insertions and deletions (indels). These mutational outcomes contribute to antibody affinity maturation. The mechanisms responsible for generating point mutations and indels involve the base excision repair (BER) and mismatch repair (MMR) pathways, which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur. In this regard, translesion synthesis (TLS) polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions. This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM. Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies (bnAbs) and autoantibodies, and has implications for vaccine design and therapeutics.

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来源期刊
CiteScore
15.10
自引率
8.80%
发文量
2907
审稿时长
3.2 months
期刊介绍: Science China Life Sciences is a scholarly journal co-sponsored by the Chinese Academy of Sciences and the National Natural Science Foundation of China, and it is published by Science China Press. The journal is dedicated to publishing high-quality, original research findings in both basic and applied life science research.
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