Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination
Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination
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DOI：
10.1073/pnas.0502779102
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发表时间：
2005-09-13
影响因子：
11.1
通讯作者：
Schatz, DG
中科院分区：
文献类型：
--
作者：
Rush, JS;Liu, M;Schatz, DG
类开关重组（CSR）是B细胞改变其Ig分子的效应功能特性的过程。切换到特定Ig同型的决定主要由B细胞活化模式和细胞因子暴露决定。最近的研究表明，转换的可能性或概率随着细胞的连续分裂而增加，并且在很大程度上与时间无关。我们利用细胞分裂作为参考点，分析了CSR的不同分子特征，试图深入了解分裂连锁开关的机制。我们的研究结果表明，靶向CSR的Ig重链常数区域的可及性是在细胞经历一次细胞分裂后建立的，并且在随后的细胞分裂中没有显著变化。相反，激活诱导的环素脱氨酶（AID） mRNA的表达随着细胞分裂的增加而增加，与CSR的频率有显著的相关性。在一个特定的分裂中，AID的水平在不同的时间点保持不变，这强烈表明AID的表达调控与分裂相关，与时间无关。此外，来自转基因的组成性AID表达加速了分裂连锁CSR。因此，我们提出分裂连锁的AID表达增加为分裂连锁的CSR提供了潜在的分子解释。
Class switch recombination (CSR) is the process by which B cells alter the effector function properties of their Ig molecules. The decision to switch to a particular Ig isotype is determined primarily by the mode of B cell activation and cytokine exposure. More recent work indicates that the likelihood or probability of switching increases with successive cell divisions and is largely independent of time. We have analyzed different molecular features of CSR using cell division as a reference point in an attempt to gain insight into the mechanism of division-linked switching. Our results indicated that the accessibility of Ig heavy chain constant regions targeted for CSR was established after the cells had undergone a single cell division and did not vary significantly with subsequent cell divisions. In contrast, expression of activation-induced cyticline deaminase (AID) mRNA was found to increase with successive divisions, exhibiting a striking correlation with the frequency of CSR. Levels of AID in a given division remained constant at different time points, strongly suggesting that the regulation of AID expression was division-linked and independent of time. In addition, constitutive AID expression from a transgene accelerated division-linked CSR. Thus, we propose that the division-linked increase in AID expression provides an underlying molecular explanation for division-linked CSR.