Requirement of non-canonical activity of uracil DNA glycosylase for class switch recombination
Requirement of non-canonical activity of uracil DNA glycosylase for class switch recombination
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DOI：
10.1074/jbc.m607439200
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发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
--
作者：
Begum, Nasim A.;Izumi, Nakako;Honjo, Tasuku
类别转换重组 (CSR) 需要激活诱导的胞苷脱氨酶 (AID) 和尿嘧啶 DNA 糖基化酶 (UNG)。 AID 参与 CSR 的 DNA 切割步骤，但 UNG 的确切作用尚不清楚。突变和缺失是受刺激进行 CSR 的脾 B 细胞中免疫球蛋白开关区域中失败的 DNA 切割的足迹。然而，UNG 缺陷并没有减少此类足迹的数量，这表明 UNG 对于 DNA 切割步骤是可有可无的。诱变实验表明，UNG 在 CSR 中的作用取决于其 WXXF 基序。该基序对于 UNG 与 HIV 病毒肽 Vpr 的相互作用也是必需的，Vpr 将 UNG 招募到 HIV 颗粒上。此外，外源Vpr对CSR具有显性负效应。这些结果表明，UNG 通过其 WXXF 基序被 Vpr 样宿主因子招募到 CSR 机制中，并在 DNA 切割后的 CSR 步骤中发挥新的非规范作用。
Activation-induced cytidine deaminase (AID) and uracil DNA glycosylase (UNG) are required for class switch recombination (CSR). AID is involved in the DNA cleavage step of CSR, but the precise role of UNG is not yet understood. Mutations and deletions are footprints of abortive DNA cleavage in the immunoglobulin switch region in splenic B cells stimulated to undergo CSR. However, a UNG deficiency did not reduce the number of such footprints, indicating UNG is dispensable for the DNA cleavage step. Mutagenesis experiments revealed that the role of UNG in CSR depends on its WXXF motif This motif is also essential for the interaction of UNG with the HIV viral peptide Vpr, which recruits UNG to the HIV particle. Furthermore, exogenous Vpr had a dominant-negative effect on CSR. These results suggest that UNG is recruited to the CSR machinery through its WXXF motif by a Vpr-like host factor and plays a novel non-canonical role in a CSR step that follows DNA cleavage.