Destabilization of human alpha-globin mRNA by translation anti-termination is controlled during erythroid differentiation and is paralleled by phased shortening of the Poly(A) tail
Destabilization of human alpha-globin mRNA by translation anti-termination is controlled during erythroid differentiation and is paralleled by phased shortening of the Poly(A) tail
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DOI：
10.1074/jbc.272.10.6607
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发表时间：
1997-03-07
影响因子：
4.8
通讯作者：
Liebhaber, SA
中科院分区：
文献类型：
--
作者：
Morales, J;Russell, JE;Liebhaber, SA
在红细胞分化过程中，珠蛋白mRNA的异常稳定性使其积累超过细胞总mRNA的95%。人类α -珠蛋白mRNA的稳定性与其序列特异性核糖核蛋白复合物在其3'-非翻译区组装有关，自然发生的抗终止突变Constant Spring （CS）允许核糖体进入α -珠蛋白mRNA的3'-非翻译区，导致mRNA加速衰变，为了研究这种不稳定的体内机制，我们建立了携带人类α (CS)基因的转基因小鼠系。与野生型人α -珠蛋白mRNA （α (wt)）相比，α (CS) mRNA在骨髓红细胞中是不稳定的，α (CS)和α (wt) mRNA的多聚(A)尾均呈现20-25个核苷酸的周期性，与多聚(A)结合蛋白的阶段性结合一致，但不稳定α (CS) mRNA的多聚(A)尾的平均长度明显短于α (wt) mRNA。α (wt)和α (CS) mRNA在外周网状细胞中具有相同的稳定性，它们各自的poly(A)尾巴同步缩短。这些发现表明，在α -珠蛋白mRNA的正常和加速衰变过程中，poly(A)尾巴在α -珠蛋白mRNA上的特征性组织得以维持，poly(A)代谢与抗终止介导的加速mRNA周转之间存在相关性，以及在红系末端分化过程中mRNA衰变机制的开关。
The extraordinary stability of globin mRNAs permits their accumulation to over 95% of total cellular mRNA during erythroid differentiation. The stability of human alpha-globin mRNA correlates with assembly of a sequence-specific ribonucleoprotein complex at its 3'-untranslated region, A naturally occurring anti-termination mutation, Constant Spring (CS), which permits ribosomes to enter the 3'-untranslated region of the alpha-globin mRNA, results in accelerated mRNA decay, To study the mechanism of this destabilization in vivo, we established transgenic mouse lines carrying the human alpha(CS) gene, Relative to wild type human alpha-globin mRNA (alpha(wt)), alpha(CS) mRNA is destabilized in marrow erythroid cells, The poly(A) tails of both the alpha(CS) and alpha(wt) mRNAs show a periodicity of 20-25 nucleotides consistent with phased binding of poly(A) binding proteins, However, the mean size of poly(A) tails of the unstable alpha(CS) mRNA is significantly shorter than that of the alpha(wt) mRNA, Unexpectedly, the alpha(wt) and alpha(CS) mRNAs are of equal stability in peripheral reticulocytes, where their respective poly(A) tails shorten coordinately, These findings demonstrate a characteristic organization of the poly(A) tail on alpha-globin mRNA which is maintained during normal and accelerated decay, a correlation between poly(A) metabolism and anti-termination-mediated accelerated mRNA turnover, and a switch in the mechanism of mRNA decay during erythroid terminal differentiation.