Key Points
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Oncogenic signalling rewires the translational machinery to support the expression of specific functional classes of pro-tumorigenic genes.
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An expanding list of structural and sequence-specific cis-regulatory elements control expression of the oncogenic translation programme.
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Specific trans-acting factors, such as RNA-binding proteins, interact with cis-regulatory elements to dictate mRNA translation in cancer cells.
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Tumour cells alter tRNA expression and modification patterns to match the codon-usage bias of mRNA networks that support the transformed phenotype.
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Translational control is crucial for the adaptive response to tumour-associated stress and represents a new therapeutic target for selectively killing cancer cells.
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Recent technological advances in profiling genome-wide translation, RNA–protein interactions, RNA structure, RNA modifications and tRNA expression are driving a new understanding of the molecular mechanisms underlying translational control in cancer.
Abstract
The past several years have seen dramatic leaps in our understanding of how gene expression is rewired at the translation level during tumorigenesis to support the transformed phenotype. This work has been driven by an explosion in technological advances and is revealing previously unimagined regulatory mechanisms that dictate functional expression of the cancer genome. In this Review we discuss emerging trends and exciting new discoveries that reveal how this translational circuitry contributes to specific aspects of tumorigenesis and cancer cell function, with a particular focus on recent insights into the role of translational control in the adaptive response to oncogenic stress conditions.
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Change history
06 April 2017
In this Review, in Figure 1, for both the figure and figure legend 'eIF4B' was incorrectly labelled as 'eIF2B'. The paper has been corrected online.
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Acknowledgements
The authors thank M. Barna for critical discussion and reading of the manuscript. This work was supported by funding from the US National Institutes of Health (R01 CA140456, R01 CA184624, R01 DK098057, R01 CA154916, RO1 HL119439 and PO1 CA165997). The authors apologize to those whose work could not be mentioned owing to space limitations. D.R. is a Leukaemia and Lymphoma Society Scholar.
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Glossary
- mTOR
-
A serine/threonine kinase that forms two distinct molecular complexes (mTORC1 and mTORC2) and acts as a master regulator of protein synthesis, largely through mTORC1-dependent phosphorylation of eukaryotic translation initiation factor 4E-binding proteins (4EBPs) and ribosomal protein S6 kinase.
- tRNA
-
Non-coding RNA with a unique L-shaped tertiary structure that contains a 'charged' amino acid covalently linked to the tRNA by aminoacyl transferases at one end and the tRNA anticodon loop that recognizes distinct mRNA codons through base-pairing interactions at the other end.
- Internal ribosome entry site
-
(IRES). A complex structural element first discovered and characterized in viruses that facilitates translation initiation by recruiting the 40S ribosome to the mRNA in a cap-independent manner frequently aided by specific RNA-binding proteins known as IRES trans-acting factors (ITAFs).
- Messenger ribonucleoprotein (mRNP) complex
-
A complex of mRNA and RNA-binding proteins that can vary throughout the life of the mRNA and act to either promote or inhibit mRNA splicing, stability and translation depending on the nature of the bound proteins.
- Upstream open reading frame
-
(uORF). An ORF comprising a start codon upstream of the primary ORF with an in-frame stop codon that can lie either 5′ or 3′ of the primary start codon. uORFs typically block translation of downstream ORFs, as ribosomes generally initiate translation at the first start codon they encounter and then disassociate from the mRNA upon translation termination.
- Alternative cleavage and polyadenylation
-
(APA). A mechanism for generating mRNAs with different lengths of 3′ untranslated region that relies on the recognition of alternative poly(A) signals in association with U- and GU-rich downstream sequence elements by the cleavage and polyadenylation specificity factor (CPSF) complex and the cleavage stimulating factor (CSTF) complex.
- Programmed translational readthrough
-
(PTR). A phenomenon that enables translation to continue past the normal stop codon in favour of termination at a downstream stop codon, potentially generating an elongated protein with a novel 3′ extension.
- 5′-terminal oligopyrimidine tract
-
(5′TOP). A sequence-specific element located at the +1 position of the 5′ untranslated region that consists of a 5′ cytosine residue followed by a stretch of 7–13 pyrimidine nucleotides.
- Pyrimidine-rich translational element
-
(PRTE). A 5′ untranslated region (5′UTR) sequence-specific motif related to the 5′-terminal oligopyrimidine tract that is not restricted to the +1 position of the 5′UTR and contains an invariant uridine at position 6 flanked by pyrimidines.
- Ribosomopathies
-
Inherited human cancer susceptibility disorders — such as cartilage–hair hypoplasia syndrome, Shwachman–Diamond syndrome, 5q deletion syndrome, dyskeratosis congenita and Diamond–Blackfan anaemia — that are characterized by mutations in distinct components of the translational machinery, including enzymes involved in the modification and processing of rRNA, ribosome assembly factors and ribosomal proteins.
- Methionine initiator tRNA
-
(tRNAiMet). A distinct species of tRNA charged with methionine that interacts with the ribosome P site as part of the eIF2–GTP–Met-tRNAiMet ternary complex that initiates translation at start codons.
- Wobble position
-
The first position in a tRNA anticodon loop that can enable non-Watson–Crick base interactions with the third nucleotide in the codon triplet and be a site for tRNA modifications.
- Unfolded protein response
-
(UPR). A conserved pathway activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) that signals through three downstream effector arms (PRKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α) and activating transcription factor 6 (ATF6)) to either relieve protein misfolding stress in the ER through increased production of chaperone proteins, enhanced protein degradation and dampened protein synthesis or commit the cell to apoptosis if stress is unresolvable.
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Truitt, M., Ruggero, D. New frontiers in translational control of the cancer genome. Nat Rev Cancer 16, 288–304 (2016). https://doi.org/10.1038/nrc.2016.27
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DOI: https://doi.org/10.1038/nrc.2016.27
