免疫球蛋白基因(Ig)容易频繁发生变异的原因

免疫球蛋白是球蛋白家族中的一员，是免疫系统中的淋巴球用于攻击外来物并保护人体的一种抗体分子，然而，与其他基因相比，负责编码免疫球蛋白的免疫球蛋白基因(Ig)更容易频繁发生变异，为什么呢？如今，研究人员们发现一些线索，可以解释Ig频繁发生变异的原因，新成果发表在12月在线出版的《自然—免疫学》期刊上。
　　在一种活化诱导胞啶核苷脱氨酶(AID)的引导下，Ig基因被一种程序化变异过程高度多样化。尽管AID总是优先倾向于靶向Ig，其他基因也能被AID异化，而且，AID所引导的异化还会导致B细胞淋巴瘤和其他恶性肿瘤的发展。
　　为了查明AID征募的机制，Rafael  Casellas和Michel  Nussenzweig合作，联合绘制了遍及全基因组的AID结合位点图。令人吃惊的是，AID的结合位点杂乱无章，比如，在与转录活性基因上的静态RNA聚合酶复合体相关的位点上，它与数千非Ig均有接合，这可以解释AID调控变异的脱靶标现象。Ig也会特别征集其他因子如RPA形成复合体，这种复合体与Ig频繁发生的变化有关。
　　推荐原文出处：
　　Nature Immunology doi:10.1038/ni.1964
　　Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes
　　Arito Yamane,Wolfgang Resch,Nan Kuo,Stefan Kuchen,Zhiyu Li,Hong-wei Sun,Davide F Robbiani,Kevin McBride,Michel C Nussenzweig& Rafael Casellas
　　The cytidine deaminase AID hypermutates immunoglobulin genes but can also target oncogenes, leading to tumorigenesis. The extent of AID”s promiscuity and its predilection for immunoglobulin genes are unknown. We report here that AID interacted broadly with promoter-proximal sequences associated with stalled polymerases and chromatin-activating marks. In contrast, genomic occupancy of replication protein A (RPA), an AID cofactor, was restricted to immunoglobulin genes. The recruitment of RPA to the immunoglobulin loci was facilitated by phosphorylation of AID at Ser38 and Thr140. We propose that stalled polymerases recruit AID, thereby resulting in low frequencies of hypermutation across the B cell genome. Efficient hypermutation and switch recombination required AID phosphorylation and correlated with recruitment of RPA. Our findings provide a rationale for the oncogenic role of AID in B cell malignancy.
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