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上海士鋒生物關(guān)于免疫球蛋白基因（Ig）容易頻繁發(fā)生變異的介紹
點(diǎn)擊次數(shù)：1174 發(fā)布時(shí)間：2013-6-13
免疫球蛋白是球蛋白家族中的一員，是免疫系統(tǒng)中的淋巴球用于攻擊外來物并保護(hù)人體的一種抗體分子，然而，與其他基因相比，負(fù)責(zé)編碼免疫球蛋白的免疫球蛋白基因（Ig）更容易頻繁發(fā)生變異，為什么呢？如今，研究人員們發(fā)現(xiàn)一些線索，可以解釋Ig頻繁發(fā)生變異的原因，新成果發(fā)表在12月在線出版的《自然—免疫學(xué)》期刊上。
在一種活化誘導(dǎo)胞啶核苷脫氨酶（AID）的引導(dǎo)下，Ig基因被一種程序化變異過程高度多樣化。盡管AID總是優(yōu)先傾向于靶向Ig，其他基因也能被AID異化，而且，AID所引導(dǎo)的異化還會(huì)導(dǎo)致B細(xì)胞淋巴瘤和其他惡性腫瘤的發(fā)展。
為了查明AID征募的機(jī)制，Rafael Casellas和Michel Nussenzweig合作，聯(lián)合繪制了遍及全基因組的AID結(jié)合位點(diǎn)圖。令人吃驚的是，AID的結(jié)合位點(diǎn)雜亂無章，比如，在與轉(zhuǎn)錄活性基因上的靜態(tài)RNA聚合酶復(fù)合體相關(guān)的位點(diǎn)上，它與數(shù)千非Ig均有接合，這可以解釋AID調(diào)控變異的脫靶標(biāo)現(xiàn)象。Ig也會(huì)特別征集其他因子如RPA形成復(fù)合體，這種復(fù)合體與Ig頻繁發(fā)生的變化有關(guān)。
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.