Preventing AID, a physiological mutator, from deleterious activation: regulation of the genomic instability that is associated with antibody diversity
Preventing AID, a physiological mutator, from deleterious activation: regulation of the genomic instability that is associated with antibody diversity
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DOI：
10.1093/intimm/dxq023
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
--
作者：
Nagaoka, Hitoshi;Tran, Thinh Huy;Honjo, Tasuku
激活诱导的胞苷脱氨酶（AID）是必不可少的，足以完成类转换重组和体细胞超突变，这是产生抗体介导的记忆反应所需的两个遗传事件。然而，AID也可引入基因组不稳定性，引起染色体易位和/或原癌基因突变。因此，除非B淋巴细胞被病原体刺激，否则细胞抑制AID表达是重要的。用于避免AID的意外激活并由此避免基因组不稳定性的机制可以分为三种类型：（i）转录调节，（ii）转录后调节和（iii）靶特异性。本文综述了最近阐明的全面的转录调控机制的AID基因和转录后调控，可能是至关重要的，以防止多余的AID活动。最后，我们讨论了为什么艾滋病的目标不仅免疫球蛋白，但也有其他原癌基因。AID靶向许多基因，但它并不完全是混杂的，并且指定其靶点的标准也不清楚。最近的一项研究发现，拓扑异构酶1表达减少后形成的非B DNA结构可能解释了这种自相矛盾的靶特异性决定。进化选择AID作为IG基因的突变体，因为它具有高效的DNA切割活性，尽管它的存在会增加基因组不稳定的风险。这可能是因为对病原体的直接保护对于物种生存来说比对基因组不稳定性的缓慢作用后果（如肿瘤形成）的完全保护更重要。
Activation-induced cytidine deaminase (AID) is essential and sufficient to accomplish class-switch recombination and somatic hypermutation, which are two genetic events required for the generation of antibody-mediated memory responses. However, AID can also introduce genomic instability, giving rise to chromosomal translocation and/or mutations in proto-oncogenes. It is therefore important for cells to suppress AID expression unless B lymphocytes are stimulated by pathogens. The mechanisms for avoiding the accidental activation of AID and thereby avoiding genomic instability can be classified into three types: (i) transcriptional regulation, (ii) post-transcriptional regulation and (iii) target specificity. This review summarizes the recently elucidated comprehensive transcriptional regulation mechanisms of the AID gene and the post-transcriptional regulation that may be critical for preventing excess AID activity. Finally, we discuss why AID targets not only Igs but also other proto-oncogenes. AID targets many genes but it is not totally promiscuous and the criteria that specify its targets are unclear. A recent finding that a non-B DNA structure forms upon a decrease in topoisomerase 1 expression may explain this paradoxical target specificity determination. Evolution has chosen AID as a mutator of Ig genes because of its efficient DNA cleavage activity, even though its presence increases the risk of genomic instability. This is probably because immediate protection against pathogens is more critical for species survival than complete protection from the slower acting consequences of genomic instability, such as tumor formation.