A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly
A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly
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DOI：
10.1038/ncb2264
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发表时间：
2011-07-01
影响因子：
21.3
通讯作者：
Buchholz, Frank
中科院分区：
文献类型：
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作者：
Krastev, Dragomir B.;Slabicki, Mikolaj;Buchholz, Frank
肿瘤蛋白53(Tumour Protein 53，TP53)是人类肿瘤中最常见的突变基因之一，其在细胞转化中的作用已被广泛研究。然而，人们对P53的稳态功能知之甚少。在这里，我们通过RNAi介导的合成相互作用筛选，使用两个HCT116等基因细胞系和基因组规模的内切核酸酶准备的短干扰RNA文库来探索TP53的分子依赖网络。我们发现了各种TP53的合成相互作用，揭示了p53与细胞生理和生长控制的复杂联系。对TP53与社发IP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，我们发现它是一个生理性的p53靶基因。TP53在snoRNP组装中的这种意想不到的功能突显了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。
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.