Opinion

Ribosome biogenesis in cancer: new players and therapeutic avenues

Published online:

Abstract

The ribosome is a complex molecular machine composed of numerous distinct proteins and nucleic acids and is responsible for protein synthesis in every living cell. Ribosome biogenesis is one of the most multifaceted and energy- demanding processes in biology, involving a large number of assembly and maturation factors, the functions of which are orchestrated by multiple cellular inputs, including mitogenic signals and nutrient availability. Although causal associations between inherited mutations affecting ribosome biogenesis and elevated cancer risk have been established over the past decade, mechanistic data have emerged suggesting a broader role for dysregulated ribosome biogenesis in the development and progression of most spontaneous cancers. In this Opinion article, we highlight the most recent findings that provide new insights into the molecular basis of ribosome biogenesis in cancer and offer our perspective on how these observations present opportunities for the design of new targeted cancer treatments.

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Acknowledgements

The authors thank A. Gentilella, R. Loewith, C. Munoz-Pinedo, D. Ruggero, J. Warner and R. White for providing insights and comments during the preparation of this manuscript. G.T.'s laboratory is funded by grants from the Asociación Española Contra el Cáncer (AECC) (grant GCB14-2035), Instituto de Salud Carlos III (ISCIII) (grants IIS10/00015), the Spanish Ministry of Science and Innovation (grant SAF2011-24967), the Career Integration Grants (CIG) European Commission (grant PCIG10-GA-2011-304160), the US National Institutes of Health (NIH)/National Cancer Institute (NCI) (grant R01-CA158768), ISCIII-Red Temática de Investigación Cooperativa en Cáncer (RTICC) (grants RD12/0036/0049), Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (grant SGR 870) and Ministerio de Economía y Competitividad, ISCIII (grant PIE13/00022). S.V.'s laboratory is funded by the Croatian Science Foundation (CSF) (grant 2079), and J.P. is supported by a Juan de la Cierva Fellowship (FJCI-2014-20422). The authors apologize to those whose work could not be cited because of space limitations.

Author information

Affiliations

  1. Joffrey Pelletier is at the Laboratory of Cancer Metabolism, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

    • Joffrey Pelletier
  2. George Thomas is at the Laboratory of Cancer Metabolism, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; at the Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA; and at the Unit of Biochemistry, Department of Physiological Sciences II, Faculty of Medicine, Campus Universitari de Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

    • George Thomas
  3. Siniša Volarević is at the Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, Croatia; and at the Scientific Center of Excellence for Reproductive and Regenerative Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, Croatia.

    • Siniša Volarević

Authors

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Contributions

The authors contributed equally to this manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to George Thomas or Siniša Volarević.

Glossary

5′-Terminal oligopyrimidine tract

(5′TOP). A specific mRNA sequence that contains a cytosine at the transcriptional start site followed by a stretch of 4 to 13 pyrimidine nucleotides.

7-Methylguanylate-cap-dependent mRNA translation

The prevalent mode of translation initiation in eukaryotic cells, mediated by binding of the eukaryotic translation initiation factor 4E (eIF4E) to the 5′ end of an mRNA via the 7-methylguanylate-cap structure (m7GpppN, where N is any nucleotide), which recruits the 40S ribosome to mRNAs.

Common fragile sites

(CFS). Unstable chromosomal regions that preferentially break or form gaps during metaphase.

G-quadruplex DNA

(G4 DNA). A stable secondary helical structure formed in G-rich nucleic acid sequences and consisting of one or more square planar structures (called tetrads) formed by guanine hydrogen bonds. The G4 structures can form intramolecularly or intermolecularly from DNA strands in parallel or in antiparallel positions.

Homologous recombination

A DNA double-strand break repair process that uses a homologous DNA sequence as a template for repair.

Internal ribosome entry site

(IRES). An RNA structural element that facilitates translation initiation by recruiting 40S ribosomes to an internal position in eukaryotic mRNAs in a cap-independent manner.

I-PpoI

A homing endonuclease from Physarum polycephalum that recognizes and cleaves a 15-base pair sequence present in 47S and 5S ribosomal DNA genes as well as 12 other sites in the human genome.

Non-homologous end joining

(NHEJ). A DNA double-strand break repair process that modifies broken ends and ligates them without the participation of a homologous DNA sequence.

Polysomes

Complexes of an mRNA with two or more ribosomes.

Ribosomal DNA

(rDNA). A region in the nucleolus containing genes whose transcription by RNA polymerase I gives rise to the precursor 47S ribosomal RNA.

Ribosome profiling

Also known as ribosome footprinting or Ribo-Seq. A genome-wide, quantitative technique that uses deep sequencing of mRNA fragments protected by ribosomes from nuclease digestion.

Ribosomopathies

Inherited human disorders caused by mutations in genes encoding ribosome components, or ribosome biogenesis factors, leading to impaired ribosome biogenesis or function.

Unequal sister chromatid exchange

The non-reciprocal exchange of a nucleotide sequence that occurs between repeated sequences present at non-equivalent locations on sister chromatids.