系统 RNAi 合成相互作用筛选揭示了 p53 和 snoRNP 组装之间的联系。
A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly.
机构信息
University of Technology Dresden, University Hospital and Medical Faculty Carl Gustav Carus, Department of Medical Systems Biology, Fetscherstraße 74, D-01307 Dresden, Germany.
出版信息
Nat Cell Biol. 2011 Jun 5;13(7):809-18. doi: 10.1038/ncb2264.
TP53 (tumour protein 53) is one of the most frequently mutated genes in human cancer and its role during cellular transformation has been studied extensively. However, the homeostatic functions of p53 are less well understood. Here, we explore the molecular dependency network of TP53 through an RNAi-mediated synthetic interaction screen employing two HCT116 isogenic cell lines and a genome-scale endoribonuclease-prepared short interfering RNA library. We identify a variety of TP53 synthetic interactions unmasking the complex connections of p53 to cellular physiology and growth control. Molecular dissection of the TP53 synthetic interaction with UNRIP indicates an enhanced dependency of TP53-negative cells on small nucleolar ribonucleoprotein (snoRNP) assembly. This dependency is mediated by the snoRNP chaperone gene NOLC1 (also known as NOPP140), which we identify as a physiological p53 target gene. This unanticipated function of TP53 in snoRNP assembly highlights the potential of RNAi-mediated synthetic interaction screens to dissect molecular pathways of tumour suppressor genes.
TP53（肿瘤蛋白 53）是人类癌症中最常发生突变的基因之一，其在细胞转化过程中的作用已被广泛研究。然而，p53 的体内平衡功能还不太清楚。在这里，我们通过使用两个 HCT116 同基因细胞系和一个全基因组内切核糖核酸酶制备的短干扰核糖核酸文库，通过 RNAi 介导的合成相互作用筛选来探索 TP53 的分子依赖网络。我们鉴定了多种 TP53 合成相互作用，揭示了 p53 与细胞生理学和生长控制的复杂联系。TP53 与 UNRIP 的合成相互作用的分子剖析表明，TP53 阴性细胞对小核仁核糖核蛋白（snoRNP）组装的依赖性增强。这种依赖性是由 snoRNP 伴侣基因 NOLC1（也称为 NOPP140）介导的，我们将其鉴定为生理 p53 靶基因。TP53 在 snoRNP 组装中的这种意外功能突出了 RNAi 介导的合成相互作用筛选在剖析肿瘤抑制基因的分子途径方面的潜力。
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