Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
J Exp Med. 2010 Feb 15;207(2):405-15. doi: 10.1084/jem.20090821. Epub 2010 Jan 25.
The process of somatic hypermutation (SHM) of immunoglobulin (Ig) genes requires activation-induced cytidine deaminase (AID). Although mistargeting of AID is detrimental to genome integrity, the mechanism and the cis-elements responsible for targeting of AID are largely unknown. We show that three CAGGTG cis-elements in the context of Ig enhancers are sufficient to target SHM to a nearby transcribed gene. The CAGGTG motif binds E47 in nuclear extracts of the mutating cells. Replacing CAGGTG with AAGGTG in the construct without any other E47 binding site eliminates SHM. The CA versus AA effect requires AID. CAGGTG does not enhance transcription, chromatin acetylation, or overall target gene activity. The other cis-elements of Ig enhancers alone cannot attract the SHM machinery. Collectively with other recent findings, we postulate that AID targets all genes expressed in mutating B cells that are associated with CAGGTG motifs in the appropriate context. Ig genes are the most highly mutated genes, presumably because of multiple CAGGTG motifs within the Ig genes, high transcription activity, and the presence of other cooperating elements in Ig enhancers.
体细胞高频突变（SHM）过程需要激活诱导胞嘧啶脱氨酶（AID）。尽管 AID 的错误靶向对基因组完整性有害，但靶向 AID 的机制和顺式元件在很大程度上仍是未知的。我们发现，在 Ig 增强子背景下的三个 CAGGTG 顺式元件足以将 SHM 靶向到附近转录的基因。CAGGTG 基序在发生突变的细胞的核提取物中与 E47 结合。在没有任何其他 E47 结合位点的构建体中用 AAGGTG 替换 CAGGTG 会消除 SHM。CA 与 AA 的影响需要 AID。CAGGTG 不会增强转录、染色质乙酰化或整体靶基因活性。Ig 增强子的其他顺式元件本身不能吸引 SHM 机制。与最近的其他发现一起，我们推测 AID 靶向所有在发生突变的 B 细胞中表达的基因，这些基因在适当的上下文中与 CAGGTG 基序相关。Ig 基因是突变率最高的基因，这可能是因为 Ig 基因内有多个 CAGGTG 基序、高转录活性以及 Ig 增强子中存在其他协同元件。
