Historically, the ribosome has been viewed as a constitutive molecular machine with little regulatory capacity in mRNA translation. However, recent findings suggest that ribosome composition and activity may be more dynamically regulated to impart a new layer of specificity in the control of gene expression.
Studies in several species have shown that 'specialized ribosomes' may exist, and that these ribosomes display heterogeneity in the composition and post-translational modifications of subsets of ribosomal proteins, variations in ribosomal RNA (rRNA) sequences or binding to distinct ribosome-associated factors. Greater variations in the translation machinery may have an substantial impact on how the genomic template is translated into functional proteins.
Specific cis-acting 'translational regulons' within mRNAs may interface with specialized ribosomes to confer translational specificity. Examples of these elements include internal ribosomal entry sites (IRESs) and upstream open reading frames (uORFs). Moreover, even core ribosome components that show little variation may exert a more specialized activity by virtue of their interactions with these specific regulatory elements.
Regulation in ribosome activity may provide an important new layer for control of gene expression in time and space that has an effect on cell and organismal biology as well as human disease.
It will be important to conceptualize mRNA translation in the same light as transcriptional control — as a process in which enhancers or attenuators are likely to fine-tune protein abundance and that culminates in unique readouts with important biological significance.
Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than intrinsic regulatory capacity in mRNA translation. However, emerging studies reveal that ribosome activity may be highly regulated. Heterogeneity in ribosome composition resulting from differential expression and post-translational modifications of ribosomal proteins, ribosomal RNA (rRNA) diversity and the activity of ribosome-associated factors may generate 'specialized ribosomes' that have a substantial impact on how the genomic template is translated into functional proteins. Moreover, constitutive components of the ribosome may also exert more specialized activities by virtue of their interactions with specific mRNA regulatory elements such as internal ribosome entry sites (IRESs) or upstream open reading frames (uORFs). Here we discuss the hypothesis that intrinsic regulation by the ribosome acts to selectively translate subsets of mRNAs harbouring unique cis-regulatory elements, thereby introducing an additional level of regulation in gene expression and the life of an organism.
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The authors would like to thank D. Ruggero, C. Bellodi, M. McMahon, C. Stumpf and members of the Barna laboratory for discussion and critical reading of the manuscript. S.X. is supported by the Agency of Science, Technology and Research of Singapore. This work was supported by the Program for Breakthrough Biomedical Research, UCSF (to M.B.) and the National Institutes of Health (NIH) Director's New Innovator Award, 1DP2OD008509 (to M.B.).
The authors declare no competing financial interests.
A conserved organelle that assembles around ribosomal DNA genes. The nucleolus is the site of ribosomal RNA transcription and the site of ribosome subunit assembly.
Homologous genes that are separated by a duplication event and that have evolved new functions.
(Asymmetric synthesis of homothallic switching endonuclease (HO)). A gene encoding a repressor that inhibits the transcription of HO — an endonuclease that causes mating-type switching in Saccharomyces cerevisiae. ASH1 mRNA is transported to the bud before translation. In the bud, Ash1 prevents the daughter cell from switching its mating type following cell division.
Or polyribosomes; clusters of two or more ribosomes attached at different sites on the same strand of mRNA. mRNAs bound to polysomes are being actively translated.
Blocks of mesoderm on either side of the neural tube of a developing vertebrate embryo. Somites will develop into structures including the vertebrae.
- Mammalian target of rapamycin complex 2
(mTORC2). A protein kinase complex that includes mTOR, RICTOR and other proteins. mTORC2 regulates cell growth, metabolism and survival in response to environmental cues such as nutrients and growth factors.
The cellular form of Plasmodium parasites when they infect a new host.
- Expansion segments
A region of ribosomal RNA (rRNA) that has dramatically increased in length from prokaryotes to eukaryotes during evolution.
- Small nucleolar RNAs
(snoRNAs). Small RNA molecules that function in ribosome biogenesis in the nucleolus by guiding the assembly of macromolecular complexes on the target RNA to allow site-specific modifications or processing reactions to occur.
- Upstream open reading frame
(uORF). An uORF is defined by a start codon and an in-frame stop codon in the 5′ untranslated region of an mRNA.
- Shine–Dalgarno sequence
A ribosomal binding site of approximately eight nucleotides in the mRNA of bacteria, located upstream of the initiation codon. Helps to recruit the small ribosomal subunit to the mRNA to initiate protein synthesis.
- Cleft palate
A craniofacial abnormality that results from a failure to fuse the left and right palatal shelves at the midline during embryogenesis. It can be caused by several environmental and genetic factors, including defects in sonic hedgehog signalling.
- Long-term potentiation
(LTP). A long-lasting increase in the size of the postsynaptic response to synaptic transmissions. LTP is thought to be a key mechanism for learning and long-term memory formation in the brain.
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Xue, S., Barna, M. Specialized ribosomes: a new frontier in gene regulation and organismal biology. Nat Rev Mol Cell Biol 13, 355–369 (2012). https://doi.org/10.1038/nrm3359
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