TY - JOUR
T1 - SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation
AU - Vendramin, Roberto
AU - Verheyden, Yvessa
AU - Ishikawa, Hideaki
AU - Goedert, Lucas
AU - Nicolas, Emilien
AU - Saraf, Kritika
AU - Armaos, Alexandros
AU - Delli Ponti, Riccardo
AU - Izumikawa, Keichi
AU - Mestdagh, Pieter
AU - Lafontaine, Denis L J
AU - Tartaglia, Gian Gaetano
AU - Takahashi, Nobuhiro
AU - Marine, Jean-Christophe
AU - Leucci, Eleonora
N1 - Funding Information:
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—Fund André Vander Stricht—Fund 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.’s 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).
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
KW - Apoptosis Regulatory Proteins/metabolism
KW - Binding Sites
KW - Cell Compartmentation
KW - Cell Line, Tumor
KW - Cell Nucleus/metabolism
KW - Cell Proliferation/genetics
KW - Cytosol/metabolism
KW - Exoribonucleases/metabolism
KW - HEK293 Cells
KW - Humans
KW - Mitochondria/metabolism
KW - Models, Biological
KW - Neoplasms/genetics
KW - Protein Biosynthesis/genetics
KW - RNA Processing, Post-Transcriptional
KW - RNA, Long Noncoding/genetics
KW - RNA, Ribosomal/genetics
KW - RNA-Binding Proteins/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85055712402&partnerID=8YFLogxK
U2 - 10.1038/s41594-018-0143-4
DO - 10.1038/s41594-018-0143-4
M3 - Article
C2 - 30374086
VL - 25
SP - 1035
EP - 1046
JO - Nature structural & molecular biology
JF - Nature structural & molecular biology
SN - 1545-9993
IS - 11
ER -
