Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements.
Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements.
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DOI：
10.1098/rsob.160241
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发表时间：
2016-11
期刊：
影响因子：
5.8
通讯作者：
Atkins JF
中科院分区：
文献类型：
--
作者：
Wu S;Mariotti M;Santesmasses D;Hill KE;Baclaocos J;Aparicio-Prat E;Li S;Mackrill J;Wu Y;Howard MT;Capecchi M;Guigó R;Burk RF;Atkins JF
动态重新定义人和小鼠硒蛋白 P (Sepp1) mRNA 中的 10 个 UGA 以指定硒代半胱氨酸而不是终止涉及两个 3' UTR 结构元件 (SECIS)，并受硒可用性的调节。除了先前已知的位于 SECIS 2 3' 处的人类 Sepp1 mRNA 聚 (A) 添加位点之外，还鉴定了另外两个位点，其中一个位点导致 10-25% 的 mRNA 缺乏 SECIS 2。为了解决功能问题，生成了删除 SECIS 1 或 SECIS 2 或用丝氨酸密码子取代第一个 UGA 的突变小鼠。他们的饮食要么是高硒的，要么是缺硒的。突变体对从血浆中分离出的较短和较长的 Sepp1 蛋白亚型产物的比例以及活力有非常不同的影响。推断出两个 SECIS 元素对 UGA 解码在空间和功能上的独特影响。我们还通过生物信息学方法鉴定了两种具有不同 5' 序列的硒蛋白 S mRNA，预计会产生具有不同 N 末端的产物。这些结果提供了对 SECIS 功能和硒蛋白亚型多样性中 mRNA 加工的深入了解。
Dynamic redefinition of the 10 UGAs in human and mouse selenoprotein P (Sepp1) mRNAs to specify selenocysteine instead of termination involves two 3′ UTR structural elements (SECIS) and is regulated by selenium availability. In addition to the previously known human Sepp1 mRNA poly(A) addition site just 3′ of SECIS 2, two further sites were identified with one resulting in 10–25% of the mRNA lacking SECIS 2. To address function, mutant mice were generated with either SECIS 1 or SECIS 2 deleted or with the first UGA substituted with a serine codon. They were fed on either high or selenium-deficient diets. The mutants had very different effects on the proportions of shorter and longer product Sepp1 protein isoforms isolated from plasma, and on viability. Spatially and functionally distinctive effects of the two SECIS elements on UGA decoding were inferred. We also bioinformatically identify two selenoprotein S mRNAs with different 5′ sequences predicted to yield products with different N-termini. These results provide insights into SECIS function and mRNA processing in selenoprotein isoform diversity.
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