Involvement of DNase γ in the resected double-strand DNA breaks in immunoglobulin genes
Involvement of DNase γ in the resected double-strand DNA breaks in immunoglobulin genes
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DOI：
10.1016/j.bbrc.2004.11.142
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发表时间：
2005-02-04
影响因子：
3.1
通讯作者：
Kitamura, D
中科院分区：
文献类型：
--
作者：
Okamoto, M;Okamoto, N;Kitamura, D
在免疫应答过程中，免疫球蛋白可变区(V)区基因的体细胞超突变(SHM)发生在生发中心(GC)B细胞，这取决于激活诱导的胞苷脱氨酶(AID)。SHM与切除的双链DNA断裂(DSB)有关，双链DNA断裂特异地发生在表达AID的GC B细胞和CD40刺激的B细胞中的重排V区。到目前为止，与DSB有关的内切酶还没有确定。在这里，我们发现DNaseγ是DNase I家族的一员，在GC B细胞和CD40刺激的B细胞中都有表达。在突变能力强的Ramos B细胞系中过表达DNase Gamma导致V区被切除的DSB显著增加，但没有钝化的DSB。相反，选择性的DNase伽马抑制剂DR396抑制了切除的DSB的产生。这些结果表明，DNase-γ参与了与SHM相关的切除DSB的产生。(C)2004 Elsevier Inc.保留所有权利。
Somatic hypermutation (SHM) of immunoglobulin variable (V) region genes occurs in the germinal center (GC) B cells during immune responses, depending on activation-induced cytidine deaminase (AID). SHM is associated with resected double-strand DNA breaks (DSBs) which were shown to occur specifically in rearranged V regions in the GC B cells and CD40-stimulated B cells expressing AID. So far, endonucleases responsible for the DSBs have not been identified. Here we show that DNase gamma, a member of DNase I family of endonucleases, is expressed in GC B cells and CD40-stimulated B cells. Overexpression of DNase gamma in the mutation-competent Ramos B-cell line resulted in a marked increase in the resected but not blunt DSBs in the V region. Conversely, a selective DNase gamma inhibitor, DR396, suppressed the generation of the resected DSBs. These results suggest that DNase gamma is involved in the generation of resected DSBs associated with SHM. (C) 2004 Elsevier Inc. All rights reserved.