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首页> 外文期刊>Journal of Molecular Biology >R-Loop Depletion by Over-expressed RNase H1 in Mouse B Cells Increases Activation-Induced Deaminase Access to the Transcribed Strand without Altering Frequency of Isotype Switching
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R-Loop Depletion by Over-expressed RNase H1 in Mouse B Cells Increases Activation-Induced Deaminase Access to the Transcribed Strand without Altering Frequency of Isotype Switching

机译：通过在小鼠B细胞中通过过表达的RNase H1进行R环耗尽使得活化诱导的脱氨酶进入转录的链，而不改变同种型切换的频率

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Abstract R-loops, three-strand structures consisting of mRNA hybridized to the complementary DNA and a single-stranded DNA loop, are formed in switch regions on the heavy-chain immunoglobulin locus. To determine if R-loops have a direct effect on any of the steps involved in isotype switching, we generated a transgenic mouse that over-expressed RNase H1, an enzyme that cleaves the RNA of RNA/DNA hybrids in B cells. R-loops in the switch μ region were depleted by 70% in ex vivo activated splenic B cells. Frequencies of isotype switching to IgG1, IgG2b, IgG2c, and IgG3 were the same as C57BL/6 control cells. However, somatic hypermutation was increased specifically on the transcribed strand from μ–γ joins, indicating that R-loops limit activation-induced (cytosine) deaminase access to the transcribed DNA strand. Our data suggest that, in the normal G+C-rich context of mammalian class switch recombination regions, R-loops are obligatory intermediates. Processing of the R-loops is needed to remove RNA allowing activation-induced (cytosine) deaminase to promote somatic hypermutation on both DNA strands to generate double-strand DNA breaks for efficient class switch recombination. One of the two cellular RNases H may assist in this process. Graphical Abstract Display Omitted Highlights ? Importance of R-loops in isotype switching in B cells ? New transgenic mouse over-expressing RNase H1 ? Decrease in R-loops does not alter frequency of switching. ? Somatic hypermutation increased on transcribed DNA strand.
机译：摘要R-LOOPS，由与互补DNA和单链DNA环杂交的mRNA组成的三链结构形成在重链免疫球蛋白基因座上的开关区域中。为了确定R-LOOPS对同种型切换中所涉及的任何步骤的直接影响，我们产生过表达的RNase H1的转基因小鼠，该酶切割B细胞中RNA / DNA杂种的RNA的酶。开关μ区的R-LOOPS在离体活性脾脏B细胞中耗尽70％。同种型切换到IgG1，IgG2B，IgG2C和IgG3的频率与C57BL / 6控制电池相同。然而，体细胞高态比从μ-γ连接的转录链上显然增加，表明R圈限制激活诱导的（胞嘧啶）脱氨酶进入转录的DNA链。我们的数据表明，在哺乳动物级开关重组区域的正常G + C的上下文中，R圈是强制性的中间体。需要处理R环以除去允许活化诱导的（胞嘧啶）脱氨酶的RNA促进DNA链中的体细胞增强以产生高效阶级开关重组的双链DNA断裂。两个细胞RNases H中的一个可以有助于该过程。图形抽象显示省略了亮点？在B细胞中切换同种型中R圈的重要性吗？新的转基因小鼠过度表达RNase H1？ R-LOOPS的降低不会改变切换频率。还是转录的DNA股线上的体细胞型升值增加。

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