Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response.
Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response.
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DOI：
10.1074/jbc.m117.818526
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发表时间：
2018-03-23
期刊：
影响因子：
--
通讯作者：
Atkins JF
中科院分区：
文献类型：
--
作者：
Loughran G;Jungreis I;Tzani I;Power M;Dmitriev RI;Ivanov IP;Kellis M;Atkins JF
尽管病毒广泛使用终止密码子通读来扩展其基因表达，但系统生物学和比较基因组学方法最近才发现了哺乳动物通读的经过验证的实例。此前，我们对超出注释终止密码子的保守蛋白质编码特征的分析预测了几个哺乳动物基因的终止密码子通读，所有这些都已通过实验验证。四种 mRNA 显示高效的终止密码子通读，并且这些 mRNA 具有 UGA 终止密码子，紧接着是在整个脊椎动物中保守的 CUAG (UGA_CUAG)。扩展该通读基序的识别，我们在这里使用组织培养报告基因分析研究了所有先前未经测试的含有 UGA_CUAG 的人类基因的终止密码子通读。维生素 D 受体 (VDR) 编码序列注释终止密码子的通读效率为 6.7%。这是测试中最高的，但所有测试都显示出显着的通读水平。 VDR 是配体诱导转录因子核受体超家族的成员，它通过其 C 端配体结合结构域与其主要配体骨化三醇结合。通读带注释的 VDR mRNA 会产生 67 个氨基酸长的 C 端延伸，从而生成名为 VDRx 的 VDR 蛋白质形式。 VDRx 可能与 VDR 形成同二聚体和异二聚体，但与 VDR 相比，即使在其伴侣视黄醇 X 受体存在的情况下，VDRx 也表现出对骨化三醇的转录反应降低。
Although stop codon readthrough is used extensively by viruses to expand their gene expression, verified instances of mammalian readthrough have only recently been uncovered by systems biology and comparative genomics approaches. Previously, our analysis of conserved protein coding signatures that extend beyond annotated stop codons predicted stop codon readthrough of several mammalian genes, all of which have been validated experimentally. Four mRNAs display highly efficient stop codon readthrough, and these mRNAs have a UGA stop codon immediately followed by CUAG (UGA_CUAG) that is conserved throughout vertebrates. Extending on the identification of this readthrough motif, we here investigated stop codon readthrough, using tissue culture reporter assays, for all previously untested human genes containing UGA_CUAG. The readthrough efficiency of the annotated stop codon for the sequence encoding vitamin D receptor (VDR) was 6.7%. It was the highest of those tested but all showed notable levels of readthrough. The VDR is a member of the nuclear receptor superfamily of ligand-inducible transcription factors, and it binds its major ligand, calcitriol, via its C-terminal ligand-binding domain. Readthrough of the annotated VDR mRNA results in a 67 amino acid–long C-terminal extension that generates a VDR proteoform named VDRx. VDRx may form homodimers and heterodimers with VDR but, compared with VDR, VDRx displayed a reduced transcriptional response to calcitriol even in the presence of its partner retinoid X receptor.
影响因子：
3.7
作者：
Chan CS;Jungreis I;Kellis M
通讯作者：
Kellis M