SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation

Roberto Vendramin; Yvessa Verheyden; Hideaki Ishikawa; Lucas Goedert; Emilien Nicolas; Kritika Saraf; Alexandros Armaos; Riccardo Delli Ponti; Keichi Izumikawa; Pieter Mestdagh; Denis L J Lafontaine; Gian Gaetano Tartaglia; Nobuhiro Takahashi; Jean-Christophe Marine; Eleonora Leucci

doi:10.1038/s41594-018-0143-4

SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation

Roberto Vendramin, Yvessa Verheyden, Hideaki Ishikawa, Lucas Goedert, Emilien Nicolas, Kritika Saraf, Alexandros Armaos, Riccardo Delli Ponti, Keichi Izumikawa, Pieter Mestdagh, Denis L J Lafontaine, Gian Gaetano Tartaglia, Nobuhiro Takahashi, Jean-Christophe Marine, Eleonora Leucci

Research output: Contribution to journal › Article › peer-review

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
Pages (from-to)	1035-1046
Number of pages	12
Journal	Nature structural & molecular biology
Volume	25
Issue number	11
DOIs	https://doi.org/10.1038/s41594-018-0143-4
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
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41594-018-0143-4

Cite this

Vendramin, R., Verheyden, Y., Ishikawa, H., Goedert, L., Nicolas, E., Saraf, K., Armaos, A., Delli Ponti, R., Izumikawa, K., Mestdagh, P., Lafontaine, D. L. J., Tartaglia, G. G., Takahashi, N., Marine, J.-C., & Leucci, E. (2018). SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation. Nature structural & molecular biology, 25(11), 1035-1046. https://doi.org/10.1038/s41594-018-0143-4

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title = "SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation",

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.",

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",

author = "Roberto Vendramin and Yvessa Verheyden and Hideaki Ishikawa and Lucas Goedert and Emilien Nicolas and Kritika Saraf and Alexandros Armaos and {Delli Ponti}, Riccardo and Keichi Izumikawa and Pieter Mestdagh and Lafontaine, {Denis L J} and Tartaglia, {Gian Gaetano} and Nobuhiro Takahashi and Jean-Christophe Marine and Eleonora Leucci",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2018",

month = nov,

day = "1",

doi = "10.1038/s41594-018-0143-4",

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Vendramin, R, Verheyden, Y, Ishikawa, H, Goedert, L, Nicolas, E, Saraf, K, Armaos, A, Delli Ponti, R, Izumikawa, K, Mestdagh, P, Lafontaine, DLJ, Tartaglia, GG, Takahashi, N, Marine, J-C & Leucci, E 2018, 'SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation', Nature structural & molecular biology, vol. 25, no. 11, pp. 1035-1046. https://doi.org/10.1038/s41594-018-0143-4

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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

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.

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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

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DO - 10.1038/s41594-018-0143-4

M3 - Article

C2 - 30374086

SN - 1545-9993

VL - 25

SP - 1035

EP - 1046

JO - Nature structural & molecular biology

JF - Nature structural & molecular biology

IS - 11

ER -

SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation

Abstract

Funding

Keywords

UN SDGs

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