Dancing with DNA: AID embraces flexible partners.
Dancing with DNA: AID embraces flexible partners.
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与 DNA 共舞：AID 拥抱灵活的合作伙伴。
DOI：
10.1038/s41422-023-00823-1
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发表时间：
2023
期刊：
影响因子：
44.1
通讯作者：
Schatz,DavidG
中科院分区：
文献类型：
--
作者：
Wang,Jianshu;Schatz,DavidG
不同抗体库的产生对于适应性免疫系统识别广泛的病原体至关重要。两种机制是该过程的核心：V（D）J重组，其发生在B细胞发育的早期阶段，并产生免疫球蛋白（IG）基因的初始多样性;以及体细胞超突变（SHM），其驱动亲和力成熟，导致高亲和力抗体的产生。SHM发生在参与免疫反应的激活的生发中心B细胞中，由激活诱导的脱氨酶（AID）启动，后者催化单链DNA（ssDNA）模板中胞嘧啶的脱氨作用，产生驻留在DNA内的尿嘧啶。1在SHM过程中，AID被认为与RNA聚合酶2（Pol 2）结合并沿着行进，并且Pol 2介导的转录被认为是ssDNA模板的来源，这是SHM的严格要求。2SHM主要在IG重链和轻链基因可变区（IgV）中引入突变，每细胞分裂每个碱基对约10− 3个突变，这比大多数基因的自发突变率高106倍。3此外，IgV的互补决定区（CDR）比间插框架区（FR）经历更高频率的突变。4，5该过程被认为有助于亲和力成熟的效率，因为CDR中的突变可以改变抗体对抗原的结合特异性和亲和力。然而，AID也被证明会使非Ig基因座脱氨基，导致脱靶突变和染色体易位，从而导致B细胞肿瘤发生。尽管如此，非Ig基因座中的突变频率通常远低于高度突变的IgV区域。6近年来，在识别SHM中涉及的因素和确定导致引入突变的分子途径方面取得了实质性进展。相比之下，尽管为解决这一问题做出了相当大的努力，但对AID和SHM特异性靶向IG基因座的机制了解相对较少。通过AID在IgV中IG转录起始位点（TSS）下游约150-1500 bp的窗口中引入突变。6目前仍不清楚针对这一窗口的机制。尽管突变可发生在整个IgV区及其紧邻的侧翼序列中，但已显示优先靶向RGYW及其反向互补物WRCY（其中R表示腺苷（A）或鸟苷（G）; Y表示胞苷（C）或胸苷（T）; W表示A或T），这些序列被AID直接靶向并被称为RGYW。
The generation of diverse antibody repertoires is crucial for the adaptive immune system to recognize a wide range of pathogens. Two mechanisms are central to this process: V (D) J recombination, which occurs during the early stages of B cell development and generates the initial diversity of immunoglobulin (Ig) genes; and somatic hypermutation (SHM), which drives affinity maturation, leading to the production of high-affinity antibodies. SHM occurs in activated germinal center B cells engaging in an immune response and is initiated by activation-induced deaminase (AID), which catalyzes the deamination of cytosine in a single-stranded DNA (ssDNA) template, yielding a uracil residing within DNA. 1 During SHM, AID is thought to associate with and travel along with RNA polymerase 2 (Pol2), and Pol2-mediated transcription is believed to be the source of the ssDNA template, which is a strict requirement for SHM. 2SHM mainly introduces mutations in Ig heavy and light chain gene variable regions (IgV) at a rate of~ 10− 3 mutations per base pair per cell division, which is 106-fold higher than the spontaneous mutation rate in most genes. 3 Moreover, the complementarity determining regions (CDRs) of IgV undergo a higher frequency of mutations than the intervening framework regions (FRs). 4, 5 This process is thought to contribute to the efficiency of affinity maturation, as mutations in the CDRs can alter the binding specificity and affinity of the antibody for antigens. However, AID has also been shown to deaminate non-Ig loci, resulting in off-target mutations and chromosomal translocations that can contribute to B cell tumorigenesis. 6 Nonetheless, the mutation frequencies in non-Ig loci are typically much lower than those of the hypermutated IgV regions. 6 In recent years, substantial progress has been made to identify the factors involved in SHM and define the molecular pathways that result in the introduction of mutations. By contrast, relatively little is understood about the mechanisms that specifically target AID and SHM to Ig loci, despite considerable efforts to address this issue. Mutations are introduced by AID in IgV in a window of~ 150-1500 bp downstream of the Ig transcription start site (TSS). 6 The mechanisms responsible for targeting this window are still unknown. Although mutations can occur throughout IgV regions and their immediate flanking sequences, it has been shown that there is preferential targeting to RGYW and its reverse complement WRCY (where R denotes adenosine (A) or guanosine (G); Y denotes cytidine (C) or thymidine (T); and W denotes A or T), sequences that are directly targeted by AID and are referred to as