AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination

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AIDによるクラススイッチの際DNA切断を起こすのはトポイソメラーゼ1であることを発見. 京都大学プレスリリース. 2009-12-08. http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2009/091208_1.htmTo initiate class switch recombination (CSR) activation-inducedcytidine deaminase (AID) induces staggered nick cleavage in the Sregion, which lies 5 to each Ig constant region gene and is rich inpalindromic sequences. Topoisomerase 1 (Top1) controls the supercoilingof DNA by nicking, rotating, and religating one strand ofDNA. Curiously, Top1 reduction or AID overexpression causes thegenomic instability. Here, we report that the inactivation of Top1by its specific inhibitor camptothecin drastically blocked both theS region cleavage and CSR, indicating that Top1 is responsible forthe S region cleavage in CSR. Surprisingly, AID expression suppressedTop1 mRNA translation and reduced its protein level. Inaddition, the decrease in the Top1 protein by RNA-mediatedknockdown augmented the AID-dependent S region cleavage, aswell as CSR. Furthermore, Top1 reduction altered DNA structure ofthe S region. Taken together, AID-induced Top1 reduction altersS region DNA structure probably to non-B form, on which Top1 canintroduce nicks but cannot religate, resulting in S region cleavage.
2009-12-11