C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification
C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification
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DOI：
10.1101/gad.193169.112
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发表时间：
2012-09-01
影响因子：
10.5
通讯作者：
Dziembowski, Andrzej
中科院分区：
文献类型：
--
作者：
Mroczek, Seweryn;Krwawicz, Joanna;Dziembowski, Andrzej
C16orf57 编码一种功能未知的人类蛋白质，该基因突变发生在伴有中性粒细胞减少症 (PN) 的皮肤异色症中，这是一种罕见的常染色体隐性遗传疾病。有趣的是，在诊断为 Rothmund-Thomson 综合征 (RTS) 和先天性角化不良 (DC) 的患者中也观察到了 C16orf57 突变，这些突变是由涉及 DNA 修复和端粒维持的基因突变引起的。酿酒酵母的遗传筛选表明，C16orf57 的酵母直系同源物 USB1 (YLR132C) 对于 U6 小核 RNA (snRNA) 生物发生和细胞活力至关重要。 Usb1 缺失使 U6 snRNA 不稳定，导致剪接缺陷和细胞生长缺陷，而 U6 snRNA 基因 SNR6 的多个拷贝的存在可抑制这种缺陷。此外，Usb1对于U6 snRNA独特特征的产生至关重要；即3'-末端磷酸。人体细胞中的 RNAi 实验以及随后的生化和功能分析证实，与酵母类似，C16orf57 编码参与 U6 snRNA 3' 端 2',3'-环磷酸盐形成的蛋白质。先进的生物信息学预测 C16orf57 编码一种磷酸二酯酶，其假定的催化活性对其体内功能至关重要。我们的结果预测了 PN、DC 和 RTS 的意想不到的分子基础，并提供了对 U6 snRNA 3' 末端形成的深入了解。
C16orf57 encodes a human protein of unknown function, and mutations in the gene occur in poikiloderma with neutropenia (PN), which is a rare, autosomal recessive disease. Interestingly, mutations in C16orf57 were also observed among patients diagnosed with Rothmund-Thomson syndrome (RTS) and dyskeratosis congenita (DC), which are caused by mutations in genes involved in DNA repair and telomere maintenance. A genetic screen in Saccharomyces cerevisiae revealed that the yeast ortholog of C16orf57, USB1 (YLR132C), is essential for U6 small nuclear RNA (snRNA) biogenesis and cell viability. Usb1 depletion destabilized U6 snRNA, leading to splicing defects and cell growth defects, which was suppressed by the presence of multiple copies of the U6 snRNA gene SNR6. Moreover, Usb1 is essential for the generation of a unique feature of U6 snRNA; namely, the 3'-terminal phosphate. RNAi experiments in human cells followed by biochemical and functional analyses confirmed that, similar to yeast, C16orf57 encodes a protein involved in the 2',3'-cyclic phosphate formation at the 3' end of U6 snRNA. Advanced bioinformatics predicted that C16orf57 encodes a phosphodiesterase whose putative catalytic activity is essential for its function in vivo. Our results predict an unexpected molecular basis for PN, DC, and RTS and provide insight into U6 snRNA 3' end formation.