Dyskerin is Required for Tumor Cell Growth Through Mechanisms that are Independent of its Role in Telomerase and only Partially Related to its Function in Precursor rRNA Processing
Dyskerin is Required for Tumor Cell Growth Through Mechanisms that are Independent of its Role in Telomerase and only Partially Related to its Function in Precursor rRNA Processing
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DOI：
10.1002/mc.20715
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发表时间：
2011-05-01
影响因子：
4.6
通讯作者：
Lin, Ping
中科院分区：
文献类型：
--
作者：
Alawi, Faizan;Lin, Ping
Dyskerin 是掺入 H/ACA RNA 的核糖核蛋白生物合成所需的必需核仁蛋白。通过与特定的 H/ACA RNA 结合，dyskerin 在细胞中发挥其大部分影响。为此，角蛋白是端粒酶复合物的核心成分，是正常端粒维持所必需的。前体 rRNA 的转录后加工也需要 Dyskerin。种系角蛋白突变会增加癌症易感性。相反，野生型dyskerin通常在散发性癌症中过度表达并且不发生突变。然而，dykerin 对散发性肿瘤发生的贡献尚不清楚。在此描述的，我们证明RNA干扰导致的dyskerin功能的急性丧失显着降低了H/ACA RNA的稳态水平，破坏了端粒酶阳性和端粒酶阴性人类细胞系的形态并抑制了锚定非依赖性生长。出乎意料的是，dyskerin 的消耗仅暂时延迟了 rRNA 的成熟，但对总 18S 或 28S rRNA 的水平没有明显影响。相反，虽然rRNA加工缺陷通常会触发p53依赖性G（1）停滞，但角蛋白耗尽的细胞通过p53独立机制在G（2）/M中积累，这与以多极纺锤体为特征的异常有丝分裂像的积累有关。端粒酶活性和 rRNA 加工速率通常在肿瘤形成期间增加。然而，我们的累积研究结果表明，dykerin 通过不需要细胞端粒酶活性存在的机制促进肿瘤细胞生长，并且可能仅部分依赖于该蛋白质在 rRNA 加工中的作用。这些数据还强化了这样的观点：dyskerin 功能的丧失和增强可能在肿瘤发生中发挥重要作用。 (C) 2010 Wiley-Liss, Inc.
Dyskerin is an essential nucleolar protein required for the biogenesis of ribonucleoproteins that incorporate H/ACA RNAs. Through binding to specific H/ACA RNAs, dyskerin exerts most of its influence in the cell. To that end, dyskerin is a core component of the telomerase complex and is required for normal telomere maintenance. Dyskerin is also required for post-transcriptional processing of precursor rRNA. Germline dyskerin mutations increase cancer susceptibility. Conversely, wild-type dyskerin is usually over-expressed and not mutated in sporadic cancers. However, the contributions of dyskerin to sporadic tumorigenesis are unknown. Described herein, we demonstrate that acute loss of dyskerin function by RNA interference significantly reduced steady-state levels of H/ACA RNAs, disrupted the morphology and inhibited anchorage-independent growth of telomerase-positive and telomerase-negative human cell lines. Unexpectedly, dyskerin depletion only transiently delayed rRNA maturation but with no appreciable effect on the levels of total 18S or 28S rRNA. Instead, while rRNA processing defects typically trigger p53-dependent G(1) arrest, dyskerin-depleted cells accumulated in G(2)/M by a p53-independent mechanism, and this was associated with an accumulation of aberrant mitotic figures that were characterized by multi-polar spindles. Telomerase activity and the rate of rRNA processing are typically increased during neoplasia. However, our cumulative findings indicate that dyskerin contributes to tumor cell growth through mechanisms which do not require the presence of cellular telomerase activity, and which may be only partially dependent upon the protein's role in rRNA processing. These data also reinforce the notion that loss and gain of dyskerin function may play important roles in tumorigenesis. (C) 2010 Wiley-Liss, Inc.