Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair.
Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair.
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DOI：
10.1016/b978-0-12-800267-4.00001-8
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发表时间：
2014
影响因子：
--
通讯作者：
Chaudhuri, Jayanta
中科院分区：
文献类型：
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作者：
Matthews, Allysia J.;Zheng, Simin;DiMenna, Lauren J.;Chaudhuri, Jayanta
在遇到抗原时，成熟IgM阳性B淋巴细胞经历类别转换重组（CSR），其中切除编码免疫球蛋白（IG）重链（Igh）基因座的默认Cμ恒定编码基因区段的外显子并用新的恒定基因区段（称为“Ch基因”，例如，Cγ、Cε或Cα）。因此，B细胞从表达IgM变为产生IgG、IgE或伊加的细胞，其中每种抗体同种型在免疫反应期间具有不同的效应子功能。CSR是一种DNA缺失-重组反应，其通过在每个Ch基因之前的重复开关（S）序列中产生DNA双链断裂（DSB）来进行，并通过供体Sμ和受体S区域之间的末端连接来完成。CSR是一个多步反应，需要通过S区转录，DNA胞苷脱氨酶AID，和几个一般的DNA修复途径的参与，包括碱基切除修复，错配修复，和经典的非同源末端连接。在这篇综述中，我们讨论了我们目前的理解如何通过S区转录产生艾滋病介导的脱氨基和艾滋病如何参与不仅在启动的CSR，但也在脱氨基残基转化成DSBs基板。此外，我们回顾了多种过程，调节艾滋病的表达和促进其招聘专门的IG位点，以及如何失调的艾滋病特异性导致致癌易位。最后，我们总结了最近的数据，在表观遗传重编程过程中，AID在维持多能干细胞状态中的潜在作用。
Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default Cμ constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as “Ch genes”, e.g., Cγ, Cε, or Cα). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor Sμ and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming.