Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
Biomed J. 2014 Sep-Oct;37(5):269-83. doi: 10.4103/2319-4170.128734.
Activation-induced Cytidine Deaminase (AID) is an essential regulator of B cell diversification, but its full range of action has until recently been an enigma. Based on homology, it was originally proposed to be an RNA-editing enzyme, but so far, no RNA substrates are known. Rather, it functions by deaminating cytidine, and in this manner, coupled with base-excision repair or mismatch repair machinery, it is a natural mutator. This allows it to play a central role in adaptive immunity, whereby it initiates the processes of class switch recombination and somatic hypermutation to help generate a diverse and high-affinity repertoire of immunoglobulin isotypes. More recently, it has been appreciated that methylated cytidine, already known as a key epigenetic mark on DNA controlling gene expression, can also be a target for AID modification. Coupled with repair machinery, this can facilitate the active removal of methylated DNA. This activity can impact the process of cellular reprogramming, including transition of a somatic cell to pluripotency, which requires major reshuffling of epigenetic memory. Thus, seemingly disparate roles for AID in controlling immune diversity and epigenetic memory have a common mechanistic basis. However, the very activity that is so useful for B cell diversity and cellular reprogramming is dangerous for the integrity of the genome. Thus, AID expression and activity is tightly regulated, and deregulation is associated with diseases including cancer. Here, we review the range of AID functions with a focus on its mechanisms of action and regulation. Major questions remain to be answered concerning how and when AID is targeted to specific loci and how this impacts development and disease.
激活诱导胞嘧啶脱氨酶（AID）是 B 细胞多样化的重要调节因子，但直到最近，其全部作用仍不为人知。基于同源性，最初它被提议为一种 RNA 编辑酶，但迄今为止，尚未发现任何 RNA 底物。相反，它通过脱氨胞嘧啶起作用，并且以这种方式，与碱基切除修复或错配修复机制结合，它是一种天然的诱变剂。这使其能够在适应性免疫中发挥核心作用，通过该作用，它启动类别转换重组和体细胞超突变过程，有助于生成多样化和高亲和力的免疫球蛋白同种型库。最近，人们已经意识到，已经作为控制基因表达的 DNA 上的关键表观遗传标记的甲基化胞嘧啶也可以成为 AID 修饰的靶标。与修复机制结合，这可以促进甲基化 DNA 的主动去除。这种活性可以影响细胞重编程的过程，包括体细胞向多能性的转变，这需要表观遗传记忆的重大重排。因此，AID 控制免疫多样性和表观遗传记忆的看似不同的作用具有共同的机制基础。然而，对于 B 细胞多样性和细胞重编程非常有用的活性对于基因组的完整性是危险的。因此，AID 的表达和活性受到严格调节，失调与包括癌症在内的疾病有关。在这里，我们回顾了 AID 的各种功能，重点介绍了其作用机制和调节。关于如何以及何时将 AID 靶向特定基因座以及这如何影响发育和疾病，仍存在许多悬而未决的问题。
