Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells.
Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells.
复制标题
激活诱导的胞苷脱氨酶在激活的 B 细胞中的许多非 Ig 位点处诱导可重复的 DNA 断裂。
DOI：
10.1016/j.molcel.2011.01.007
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发表时间：
2011
期刊：
影响因子：
16
通讯作者：
Guikema,JeroenEJ
中科院分区：
文献类型：
--
作者：
Staszewski,Ori;Baker,RichardE;Ucher,AnnaJ;Martier,Raygene;Stavnezer,Janet;Guikema,JeroenEJ
免疫或感染后，激活诱导型胞苷脱氨酶(AID)启动B细胞免疫球蛋白(Ig)基因的多样化，将抗原结合V区(体细胞高突变)和双链DNA断裂(DSB)中的突变引入开关(S)区域，导致抗体类开关重组(CSR)。我们询问，在B细胞激活过程中，AID是否也会导致除IgH基因以外的其他基因的DNA断裂。使用一种无偏见的全基因组方法，我们已经在小鼠脾B细胞中鉴定出数百个可重复的、依赖艾滋病的DSB，在培养中诱导CSR后不久。最有趣的是，AID在与人类B细胞淋巴瘤中发现的易位、缺失和扩增位点同线的位置诱导DSB，包括在致癌的B细胞淋巴瘤11a(BCL11A)/evi9内。与免疫球蛋白基因中AID诱导的DSB不同，全基因组依赖AID的DSB不限于转录区域，而且经常出现在重复序列元件中，包括CA重复序列、非CA串联重复序列和Sine。
After immunization or infection, activation-induced cytidine deaminase (AID) initiates diversification of immunoglobulin (Ig) genes in B cells, introducing mutations within the antigen-binding V regions (somatic hypermutation, SHM) and double-strand DNA breaks (DSBs) into switch (S) regions, leading to antibody class switch recombination (CSR). We asked if, during B cell activation, AID also induces DNA breaks at genes other than IgH genes. Using a nonbiased genome-wide approach, we have identified hundreds of reproducible, AID-dependent DSBs in mouse splenic B cells shortly after induction of CSR in culture. Most interestingly, AID induces DSBs at sites syntenic with sites of translocations, deletions, and amplifications found in human B cell lymphomas, including within the oncogeneB cell lymphoma11a(bcl11a)/evi9. Unlike AID-induced DSBs in Ig genes, genome-wide AID-dependent DSBs are not restricted to transcribed regions and frequently occur within repeated sequence elements, including CA repeats, non-CA tandem repeats, and SINEs.