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

Nat Cell Biol. 2011 Jun 5;13(7):809-18. doi: 10.1038/ncb2264.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • High-Throughput Screening Assays
  • Humans
  • Microscopy, Fluorescence
  • Microscopy, Video
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • RNA Interference*
  • Ribonucleoproteins, Small Nucleolar / metabolism*
  • SMN Complex Proteins / genetics
  • SMN Complex Proteins / metabolism
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • NOLC1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Ribonucleoproteins, Small Nucleolar
  • SMN Complex Proteins
  • STRAP protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53