Impaired ribosome biogenesis in Diamond-Blackfan anemia
Impaired ribosome biogenesis in Diamond-Blackfan anemia
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DOI：
10.1182/blood-2006-07-038372
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发表时间：
2007-02-01
期刊：
影响因子：
20.3
通讯作者：
Gleizes, Pierre-Emmanuel
中科院分区：
文献类型：
--
作者：
Choesmel, Valerie;Bacqueville, Daniel;Gleizes, Pierre-Emmanuel
编码核糖体蛋白S19（RPS 19）的基因在钻石-布莱克凡贫血（DBA）（一种先天性成红细胞减少症）中经常发生突变。这些突变对疾病发作的影响仍然不清楚。在这里，我们表明，RPS 19在人类细胞中的40 S小核糖体亚基的生物合成中起着至关重要的作用。通过siRNA敲低RPS 19表达损害HeLa细胞中18 S rRNA合成和40 S亚基的形成并诱导凋亡。前rRNA加工被改变，这导致18 S rRNA前体成熟的停滞。在这些条件下，前40 S颗粒不输出到细胞质中，并在核周点的细胞的核质中积累。一致地，我们发现，核糖体生物发生和核仁组织的DBA患者在RPS 19基因突变的皮肤成纤维细胞发生改变。此外，在不携带RPS 19相关突变的患者的细胞中，18 S rRNA的成熟也会受到干扰。这些结果支持DBA与核糖体生物合成缺陷直接相关的假设，并表明尚未发现的DBA相关基因可能参与核糖体亚基的合成。
The gene encoding the ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. The consequence of these mutations on the onset of the disease remains obscure. Here, we show that RPS19 plays an essential role in biogenesis of the 40S small ribosomal subunit in human cells. Knockdown of RPS19 expression by siRNAs impairs 18S rRNA synthesis and formation of 40S subunits and induces apoptosis in HeLa cells. Pre-rRNA processing is altered, which leads to an arrest in the maturation of precursors to the 18S rRNA. Under these conditions, pre-40S particles are not exported to the cytoplasm and accumulate in the nucleoplasm of the cells in perinuclear dots. Consistently, we find that ribosome biogenesis and nucleolar organization is altered in skin fibroblasts from DBA patients bearing mutations in the RPS19 gene. In addition, maturation of the 18S rRNA is also perturbed in cells from a patient bearing no RPS19-related mutation. These results support the hypothesis that DBA is directly related to a defect in ribosome biogenesis and indicate that yet to be discovered DBA-related genes may be involved in the synthesis of the ribosomal subunits.