Evolutionary Comparison of the Mechanism of DNA Cleavage with Respect to Immune Diversity and Genomic Instability
Evolutionary Comparison of the Mechanism of DNA Cleavage with Respect to Immune Diversity and Genomic Instability
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DOI：
10.1021/bi3005895
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发表时间：
2012-07-03
期刊：
影响因子：
2.9
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
--
作者：
Begum, Nasim A.;Honjo, Tasuku
一般认为，免疫多样性的遗传机制是独特的，不同于一般的基因组多样性，部分原因是免疫多样性的高效率和严格的调节。RAG 1和RAG-2的发现部分地满足了这一期望，RAG 1和RAG-2催化V（D）J重组以产生B和T淋巴细胞受体的免疫库。RAG 1和RAG 2后来被证明来自转座子。另一方面，激活诱导的胞苷脱氨酶（AID）介导体细胞超突变（SHM）和免疫球蛋白基因的类别转换重组（CSR），在无颌脊椎动物中比RAG 1和-2更早进化。这篇综述从进化的角度比较了免疫多样性和一般基因组多样性，阐明了DNA裂解酶和靶标识别标记的作用。这一比较表明，艾滋病介导的SHM和CSR共享切割酶拓扑异构酶1与转录相关突变（TAM）和三联体收缩，这是参与许多遗传性疾病。这些基因组改变事件似乎靶向具有非B结构的DNA，这是由活性转录引起的过度超螺旋的低效校正引起的。此外，染色质上的表观遗传修饰（组蛋白H3 K4三甲基化）用作减数分裂重组、V（D）J重组、CSR和SHM中DNA切割位点的标记。我们的结论是，获得性免疫多样性的发展，通过外观的艾滋病直系同源物，利用预先存在的机制，基因组的不稳定性，如TAM。
It is generally assumed that the genetic mechanism for immune diversity is unique and distinct from that for general genome diversity, in part because of the high efficiency and strict regulation of immune diversity. This expectation was partially met by the discovery of RAG1 and -2, which catalyze V(D)J recombination to generate the immune repertoire of B and T lymphocyte receptors. RAG1 and -2 were later shown to be derived from a transposon. On the other hand, activation-induced cytidine deaminase (AID), which mediates both somatic hypermutation (SHM) and the class-switch recombination (CSR) of the immunoglobulin genes, evolved earlier than RAG1 and -2 in jawless vertebrates. This review compares immune diversity and general genome diversity from an evolutionary perspective, shedding light on the roles of DNA-cleaving enzymes and target recognition markers. This comparison revealed that AID-mediated SHM and CSR share the cleaving enzyme topoisomerase 1 with transcription-associated mutation (TAM) and triplet contraction, which is involved in many genetic diseases. These genome-altering events appear to target DNA with non-B structure, which is induced by the inefficient correction of the excessive supercoiling that is caused by active transcription. Furthermore, an epigenetic modification on chromatin (histone H3K4 trimethylation) is used as a mark for DNA cleavage sites in meiotic recombination, V(D)J recombination, CSR, and SHM. We conclude that acquired immune diversity evolved via the appearance of an AID orthologue that utilized a preexisting mechanism for genomic instability, such as TAM.