Aberrant 3′ oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia
Aberrant 3′ oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia
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DOI：
10.1182/blood-2012-10-461491
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发表时间：
2013-02-07
期刊：
影响因子：
20.3
通讯作者：
Warren, Alan J.
中科院分区：
文献类型：
--
作者：
Hilcenko, Christine;Simpson, Paul J.;Warren, Alan J.
隐性遗传性中性粒细胞减少症（PN）是由编码高度保守的USB 1蛋白的C16 orf 57基因突变引起的。在这里，我们提出了人类USB 1的1.1埃分辨率晶体结构，将其定义为LigT样2 H磷酸酯酶超家族的成员。我们发现，人USB 1是一种分布性的3 '-5'核糖核酸外切酶，它在转录后从剪接体U6小核RNA（snRNA）的3'端去除尿苷和腺苷核苷，直接催化末端2'，3'环磷酸的形成。USB 1通过阅读关键腺嘌呤核苷酸（A102）的位置并暂停下游5个尿苷残基来测量U6寡核苷酸（U）尾的适当长度。我们发现PN患者淋巴母细胞中U6 snRNA的3'末端被拉长，并意外地携带非模板化的3'寡核苷酸（A）尾，这是核RNA监视靶的特征。因此，我们的研究揭示了一种新的质量控制途径，其中USB 1的转录后3 '端加工保护U6 snRNA免受核外泌体的靶向和破坏。我们的数据暗示U6 snRNA的异常寡聚腺苷酸化在白血病易感性障碍PN的发病机制中。（血。2013;121（6）：1028-1038）
The recessive disorder poikiloderma with neutropenia (PN) is caused by mutations in the C16orf57 gene that encodes the highly conserved USB1 protein. Here, we present the 1.1 angstrom resolution crystal structure of human USB1, defining it as a member of the LigT-like superfamily of 2H phosphoesterases. We show that human USB1 is a distributive 3'-5' exoribonuclease that posttranscriptionally removes uridine and adenosine nucleosides from the 3' end of spliceosomal U6 small nuclear RNA (snRNA), directly catalyzing terminal 2', 3' cyclic phosphate formation. USB1 measures the appropriate length of the U6 oligo(U) tail by reading the position of a key adenine nucleotide (A102) and pausing 5 uridine residues downstream. We show that the 3' ends of U6 snRNA in PN patient lymphoblasts are elongated and unexpectedly carry nontemplated 3' oligo(A) tails that are characteristic of nuclear RNA surveillancetargets. Thus, our study reveals a novel quality control pathway in which posttranscriptional 3'-end processing by USB1 protects U6 snRNA from targeting and destruction by the nuclear exosome. Our data implicate aberrant oligoadenylation of U6 snRNA in the pathogenesis of the leukemia predisposition disorder PN. (Blood. 2013;121(6):1028-1038)