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A new human dyskerin isoform with cytoplasmic localization.

机译:一种新的人dyskerin亚型,具有胞质定位。

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BACKGROUND: The human DKC1 gene is causative of X-linked dyskeratosis congenita (X-DC), a syndrome characterized by mucocutaneous features, bone marrow failure, tumor susceptibility, perturbation of stem cell function, and premature aging. DKC1 is thought to produce a single protein, named dyskerin, which shows strict nucleolar localization and participates in at least two distinct nuclear functional complexes: the H/ACA small nucleolar ribonucleoproteic complex involved in RNA pseudouridylation and the active telomerase complex. METHODS: By bioinformatics and molecular analyses we identified a DKC1 splice variant able to encode a truncated form of dyskerin, confirmed its active expression in diverse human tissues by RT-PCR, and showed by immunoblotting and immunocytochemistry experiments that it actually encodes a novel protein. Stably transfected clones over-expressing the new isoform were analyzed for growth, morphology and adhesion properties. RESULTS: Our results show that DKC1 encodes a new alternatively spliced mRNA able to direct the synthesis of a variant dyskerin with unexpected cytoplasmic localization. Intriguingly, when over-expressed in HeLa cells, the new isoform promotes cell to cell and cell to substratum adhesion, increases the cell proliferation rate and leads to cytokeratin hyper-expression. CONCLUSIONS AND GENERAL SIGNIFICANCE: Our results highlight a novel degree of complexity and regulation of the human DKC1 gene and reveal that it can play a further, unpredicted role in cell adhesion. The identification of a dyskerin cytoplasmic variant reinforces the view that other mechanisms, in addition to telomere instability, can significantly contribute to the pathogenesis of the X-DC, and suggests that DKC1 nucleolar and cytoplasmic functions might cumulatively account for the plethora of manifestations displayed by this syndrome.
机译:背景:人类DKC1基因是X连锁性先天性角化病(X-DC)的病因,该综合征以皮肤粘膜特征,骨髓衰竭,肿瘤易感性,干细胞功能紊乱和过早衰老为特征。 DKC1被认为可以产生一种名为dyskerin的蛋白,该蛋白显示出严格的核仁定位并参与至少两个不同的核功能复合物:参与RNA假尿酸化的H / ACA小核仁核糖核蛋白复合物和活性端粒酶复合物。方法:通过生物信息学和分子分析,我们鉴定了DKC1剪接变体,该变体能够编码截短形式的dyskerin,通过RT-PCR确认其在多种人体组织中的有效表达,并通过免疫印迹和免疫细胞化学实验表明其实际上编码一种新蛋白。对过量表达新同工型的稳定转染的克隆进行了生长,形态和粘附特性分析。结果:我们的结果表明DKC1编码一个新的选择性剪接的mRNA,能够指导具有异常胞质定位的变体dyskerin的合成。有趣的是,当在HeLa细胞中过表达时,新的同工型会促进细胞与细胞之间以及细胞与基质之间的粘附,从而增加细胞增殖速率并导致细胞角蛋白过度表达。结论和一般意义:我们的结果突出了人类DKC1基因的复杂程度和调节的新程度,并揭示了它在细胞粘附中可以发挥进一步的,不可预测的作用。 dyskerin胞质变异体的鉴定强化了这样一种观点,即端粒不稳定性之外的其他机制也可以显着影响X-DC的发病机理,并表明DKC1的核仁和胞质功能可能累积解释了这种综合症。

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