Somatic hypermutation in the absence of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) or recombination-activating gene (RAG)1 activity
Somatic hypermutation in the absence of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) or recombination-activating gene (RAG)1 activity
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DOI：
10.1084/jem.192.10.1509
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发表时间：
2000-11-20
影响因子：
15.3
通讯作者：
Neuberger, MS
中科院分区：
文献类型：
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作者：
Bemark, M;Sale, JE;Neuberger, MS
体细胞超突变和同种型转换重组发生在生发中心B细胞中，与转录相关，并且类似地受到MutS同源物（MSH）2缺陷的影响。通过破坏编码DNA依赖性蛋白激酶（DNA-PKcs）/Ku复合物的催化亚基的组分的基因来废除类告密者重组，并且可能涉及非同源末端连接（NHEJ）。体细胞高突变也可能与末端连接有关，这是由其与产生缺失、重复和末端转移酶可接近的位点的关系所暗示的。然而，在突变过程中对NHEJ的要求尚未得到证实。在这里，我们表明，在NHEJ缺陷的小鼠体细胞突变可以通过引入重排的免疫球蛋白和T细胞受体转基因进行测试：转基因组合不仅允许重建外周淋巴室，但也允许形成生发中心，尽管在这些动物的淋巴细胞抗原受体的全单克隆性质。使用这种策略，我们证实，体细胞超突变类转换可以发生在重组激活基因（RAG）1的情况下，但表明这两个过程的不同之处在于，超突变可以进行基本上不受DNA-PKcs活性缺陷。
Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-snitch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs)/Ku complex and Likely involves nonhomologous end joining (NHEJ). That somatic hypemutation might also be associated with end joining is suggested by its association with the creation of deletions, duplications, and sites accessible to terminal transferase. However, a requirement for NHEJ in the mutation process has not been demonstrated. Here we show that somatic mutation in mice deficient in NHEJ can be tested by introduction of rearranged immunoglobulin and T cell receptor trans-genes: the transgene combination not only permits reconstitution of peripheral lymphoid compartments but also allows formation of germinal centers, despite the wholly monoclonal nature of the lymphocyte antigen receptors in these animals. Using this strategy, we confirm that somatic hypermutation like class-switching can occur in the absence of recombination-activating gene (RAG)1 but show that the two processes differ in that hypermutation can proceed essentially unaffected by deficiency in DNA-PKcs activity.