Focal deletions occur frequently in the cancer genome. However, the putative tumor-suppressive genes residing within these regions have been difficult to pinpoint. To robustly identify these genes, we implemented a computational approach based on non-negative matrix factorization, NMF, and interrogated the TCGA dataset. This analysis revealed a metagene signature including a small subset of genes showing pervasive hemizygous deletions, reduced expression in cancer patient samples, and nucleolar function. Amid the genes belonging to this signature, we have identified PNRC1, a nuclear receptor coactivator. We found that PNRC1 interacts with the cytoplasmic DCP1α/DCP2 decapping machinery and hauls it inside the nucleolus. PNRC1-dependent nucleolar translocation of the decapping complex is associated with a decrease in the 5′-capped U3 and U8 snoRNA fractions, hampering ribosomal RNA maturation. As a result, PNRC1 ablates the enhanced proliferation triggered by established oncogenes such as RAS and MYC. These observations uncover a previously undescribed mechanism of tumor suppression, whereby the cytoplasmic decapping machinery is hauled within nucleoli, tightly regulating ribosomal RNA maturation. © 2018 The Authors
|Publication status||Published - 2018|
Gaviraghi, M., Vivori, C., Pareja Sanchez, Y., Invernizzi, F., Cattaneo, A., Santoliquido, BM., Frenquelli, M., Segalla, S., Bachi, A., Doglioni, C., Pelechano, V., Cittaro, D., & Tonon, G. (2018). Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus. EMBO Journal, 37(23), [e99179].