Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus

M Gaviraghi, C Vivori, Y Pareja Sanchez, F Invernizzi, A Cattaneo, BM Santoliquido, M Frenquelli, S Segalla, A Bachi, C Doglioni, V Pelechano, D Cittaro, G Tonon

Research output: Contribution to journalArticle

Abstract

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
Original languageEnglish
Article numbere99179
JournalEMBO Journal
Volume37
Issue number23
Publication statusPublished - 2018

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Tumors
Genes
Ribosomal RNA
Neoplasms
Nuclear Receptor Coactivators
Machinery
Small Nucleolar RNA
Oncogenes
Factorization
Genome

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Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus. / 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.

In: EMBO Journal, Vol. 37, No. 23, e99179, 2018.

Research output: Contribution to journalArticle

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AU - Gaviraghi, M

AU - Vivori, C

AU - Pareja Sanchez, Y

AU - Invernizzi, F

AU - Cattaneo, A

AU - Santoliquido, BM

AU - Frenquelli, M

AU - Segalla, S

AU - Bachi, A

AU - Doglioni, C

AU - Pelechano, V

AU - Cittaro, D

AU - Tonon, G

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AB - 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

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