A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly

Abstract

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. A genome-wide RNAi synthetic lethal screen unravels the role of p53 in small nucleolar RNPs (snoRNPs) through a genetic interaction with UNRIP, which has been previously shown to interact with the snoRNP chaperone SMN. p53 regulates the levels of Nolc1, which affects snoRNP stability, whereas UNRIP contributes to nuclear SMN import, revealing a synergistic requirement for both in snoRNP assembly.

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Krastev, D., Slabicki, M., Paszkowski-Rogacz, M. et al. A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly. Nat Cell Biol 13, 809–818 (2011). https://doi.org/10.1038/ncb2264

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