Ribosomopathies: Old Concepts, New Controversies

Abstract

Ribosomopathies are a diverse subset of diseases caused by reduced expression of, or mutations in, factors necessary for making ribosomes, the protein translation machinery in the cell. Despite the ubiquitous need for ribosomes in all cell types, ribosomopathies manifest with tissue-specific defects and sometimes increased cancer susceptibility, but few treatments target the underlying cause. By highlighting new research in the field, we review current hypotheses for the basis of this tissue specificity. Based on new work, we broaden our understanding of the role of ribosome biogenesis in diverse tissue types throughout embryonic development. We also pose the question of whether previously described human conditions such as aging can be at least partially attributed to defects in making ribosomes.

Keywords: aging; cancer; neurodegeneration; ribosome concentration hypothesis; ribosomopathy; specialized ribosome.

Figure 1.

How ribosomopathies impact ribosome production. Ribosomopathies can affect: (top left) pre-ribosomal RNA (pre-rRNA) transcription and modification including pseudouridylations (ψ) and 2’-O-methylations (CH₃), (top right) pre-rRNA processing, and (bottom) ribosome assembly. Proteins named in each section are highlighted in this review, including RNAPI subunits (grey), RNAPI-associated factors (green), small subunit (SSU) components and factors (purple), and large subunit (LSU) components and factors (red).

Figure 2.

The clinical manifestations of ribosomopathies. The diverse pathologies associated with ribosomopathies are depicted. These pathologies arise from neural crest cell (red) and non-neural crest cell lineages (green).

Figure 3.

Two hypotheses for the tissue-specific effects of ribosomopathies. (Left) The specialized ribosome hypothesis states that modification or changes in rRNA sequence, core r-protein composition, or accessory proteins in either the large subunit (LSU) or small subunit (SSU) of the ribosome can result in heterogeneous ribosomes with differential translation abilities in diverse tissues. (Right) The ribosome concentration hypothesis states that decreased ribosome concentration results in decreased protein levels for specific mRNAs. At low ribosome concentrations, the original Lodish model [81] proposed that mRNAs with long, highly structured 5’ UTRs would be most affected by changes in ribosome concentration (above), whereas new data by Khajuria et al. [27] and Cheng et al. [84] propose the opposite (below).