AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination
AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination
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DOI：
10.1073/pnas.0911879106
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发表时间：
2009-12-29
影响因子：
11.1
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
--
作者：
Kobayashi, Maki;Aida, Masatoshi;Honjo, Tasuku
为了启动类别转换重组（CSR），激活诱导的胞苷脱氨酶（AID）在S区诱导交错切口切割，S区位于每个IG恒定区基因的5'端并且富含回文序列。拓扑异构酶1（Top1）通过切割、旋转和重新连接一条DNA链来控制DNA的超螺旋。奇怪的是，Top1减少或AID过表达导致基因组不稳定。在这里，我们报告说，其特异性抑制剂喜树碱的Top1的失活大大阻止了S区切割和CSR，表明Top1是负责CSR中的S区切割。令人惊讶的是，AID表达抑制Top1 mRNA翻译并降低其蛋白水平。此外，RNA介导的敲低导致Top1蛋白减少，增强了AIDS依赖性S区切割以及CSR。此外，Top1减少改变了S μ区域的DNA结构。综上所述，艾滋病诱导的Top1减少改变了S区DNA结构可能是非B的形式，Top1可以引入切口，但不能重新连接，导致S区切割。
To initiate class switch recombination (CSR) activation-induced cytidine deaminase (AID) induces staggered nick cleavage in the S region, which lies 5' to each Ig constant region gene and is rich in palindromic sequences. Topoisomerase 1 (Top1) controls the supercoiling of DNA by nicking, rotating, and religating one strand of DNA. Curiously, Top1 reduction or AID overexpression causes the genomic instability. Here, we report that the inactivation of Top1 by its specific inhibitor camptothecin drastically blocked both the S region cleavage and CSR, indicating that Top1 is responsible for the S region cleavage in CSR. Surprisingly, AID expression suppressed Top1 mRNA translation and reduced its protein level. In addition, the decrease in the Top1 protein by RNA-mediated knockdown augmented the AID-dependent S region cleavage, as well as CSR. Furthermore, Top1 reduction altered DNA structure of the S mu region. Taken together, AID-induced Top1 reduction alters S region DNA structure probably to non-B form, on which Top1 can introduce nicks but cannot religate, resulting in S region cleavage.