Discovery of activation-induced cytidine deaminase, the engraver of antibody memory.
Discovery of activation-induced cytidine deaminase, the engraver of antibody memory.
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DOI：
10.1016/s0065-2776(06)94001-2
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发表时间：
2007-01-01
影响因子：
--
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
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作者：
Muramatsu, Masamichi;Nagaoka, Hitoshi;Honjo, Tasuku
激活诱导胞苷脱氨酶（AID）的发现为结合抗原刺激引起的两种基因改变开辟了新的途径；类开关重组（CSR）和体细胞超突变（SHM）。现在已经确定AID可以切割特定的目标DNA，并作为这些遗传改变的雕刻者。198-残基蛋白的AID有四个重要结构域：核定位信号和n端shm特异性区域；负责二聚化的α -螺旋段（残基47-54）；所有胞苷脱氨酶家族成员共享催化结构域（56-94残基）；和核输出信号在c端与类开关特定域重叠。关于援助行动方式，提出了两种备选模式；AID是直接攻击DNA还是通过RNA编辑间接攻击DNA。支持RNA编辑假说的证据包括与APOBEC1（一种真正的RNA编辑酶）在各个方面的同源性，以及在CSR和SHM中AID切割DNA所需的从头合成蛋白质。本章批判性地评估了DNA脱氨假说，并描述了表明UNG不参与DNA切割而是参与CSR DNA修复的证据。此外，UNG似乎通过与WXXF基序上的HIV病毒样蛋白相互作用而具有非规范功能。综上所述，RNA编辑假说正在获得支持。
Discovery of activation-induced cytidine deaminase (AID) paved a new path to unite two genetic alterations induced by antigen stimulation; class switch recombination (CSR) and somatic hypermutation (SHM). AID is now established to cleave specific target DNA and to serve as engraver of these genetic alterations. AID of a 198-residue protein has four important domains: nuclear localization signal and SHM-specific region at the N-terminus; the alpha-helical segment (residue 47-54) responsible for dimerization; catalytic domain (residues 56-94) shared by all the other cytidine deaminase family members; and nuclear export signal overlapping with class switch-specific domain at the C-terminus. Two alternative models have been proposed for the mode of AID action; whether AID directly attacks DNA or indirectly through RNA editing. Lines of evidence supporting RNA editing hypothesis include homology in various aspects with APOBEC1, a bona fide RNA editing enzyme as well as requirement of de novo protein synthesis for DNA cleavage by AID in CSR and SHM. This chapter critically evaluates DNA deamination hypothesis and describes evidence to indicate UNG is involved not in DNA cleavage but in DNA repair of CSR. In addition, UNG appears to have a noncanonical function through interaction with an HIV Vpr-like protein at the WXXF motif. Taken together, RNA editing hypothesis is gaining the ground.