Abstract
Synchronization of mitochondrial and cytoplasmic translation rates is critical for the maintenance of cellular fitness, with cancer cells being especially vulnerable to translational uncoupling. Although alterations of cytosolic protein synthesis are common in human cancer, compensating mechanisms in mitochondrial translation remain elusive. Here we show that the malignant long non-coding RNA (lncRNA) SAMMSON promotes a balanced increase in ribosomal RNA (rRNA) maturation and protein synthesis in the cytosol and mitochondria by modulating the localization of CARF, an RNA-binding protein that sequesters the exo-ribonuclease XRN2 in the nucleoplasm, which under normal circumstances limits nucleolar rRNA maturation. SAMMSON interferes with XRN2 binding to CARF in the nucleus by favoring the formation of an aberrant cytoplasmic RNA-protein complex containing CARF and p32, a mitochondrial protein required for the processing of the mitochondrial rRNAs. These data highlight how a single oncogenic lncRNA can simultaneously modulate RNA-protein complex formation in two distinct cellular compartments to promote cell growth.
Original language | English |
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Pages (from-to) | 1035-1046 |
Number of pages | 12 |
Journal | Nature structural & molecular biology |
Volume | 25 |
Issue number | 11 |
DOIs | |
Publication status | Published - 1 Nov 2018 |
Externally published | Yes |
Funding
GapmeRs were designed by J. Lai (Exiqon, Copenhagen Denmark). We would like to thank M. Leucci for reading and editing the manuscript. This study was supported by the Fund Emile Carpentier\u2014Fund Andr\u00E9 Vander Stricht\u2014Fund Van Damme 2017-J1810830-207301. The authors wish to thank H. Brems for providing NHEM cultures, A. Sablina (VIB-KULeuven) for providing the SV40 LTA plasmid, M. Spinazzi (VIB-KULeuven) for the technical assistance and for sharing some antibodies, G. Ghanem (Jules Bordet Institute) for the patient-derived melanoma cell line and somersault18:24 (http://www.somersault1824.com/) for providing some graphical illustrations. R.V. is a recipient of the FWO PhD fellowship 1S08316N. D.L. is supported by Fonds National de la Recherche (FRS/FNRS). G.G.T.\u2019s research is supported by the European Research Council (grant no. RIBOMYLOME_309545) and the Spanish Ministry of Economy and Competitiveness (grant nos. BFU2014-55054-P and BFU2017-86970-P).
Funders | Funder number |
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Fonds Wetenschappelijk Onderzoek | |
European Commission | |
FRS | |
Fonds National de la Recherche Luxembourg | |
Fonds De La Recherche Scientifique - FNRS | |
European Research Council | |
Seventh Framework Programme | 309545 |
Ministerio de Economía y Competitividad | BFU2014-55054-P, BFU2017-86970-P |
Keywords
- Apoptosis Regulatory Proteins/metabolism
- Binding Sites
- Cell Compartmentation
- Cell Line, Tumor
- Cell Nucleus/metabolism
- Cell Proliferation/genetics
- Cytosol/metabolism
- Exoribonucleases/metabolism
- HEK293 Cells
- Humans
- Mitochondria/metabolism
- Models, Biological
- Neoplasms/genetics
- Protein Biosynthesis/genetics
- RNA Processing, Post-Transcriptional
- RNA, Long Noncoding/genetics
- RNA, Ribosomal/genetics
- RNA-Binding Proteins/metabolism