Cancer Biogenesis in Ribosomopathies

Abstract

Ribosomopathies are congenital diseases with defects in ribosome assembly and are characterized by elevated cancer risks. Additionally, somatic mutations in ribosomal proteins have recently been linked to a variety of cancers. Despite a clear correlation between ribosome defects and cancer, the molecular mechanisms by which these defects promote tumorigenesis are unclear. In this review, we focus on the emerging mechanisms that link ribosomal defects in ribosomopathies to cancer progression. This includes functional "onco-specialization" of mutant ribosomes, extra-ribosomal consequences of mutations in ribosomal proteins and ribosome assembly factors, and effects of ribosomal mutations on cellular stress and metabolism. We integrate some of these recent findings in a single model that can partially explain the paradoxical transition from hypo- to hyperproliferation phenotypes, as observed in ribosomopathies. Finally, we discuss the current and potential strategies, and the associated challenges for therapeutic intervention in ribosome-mutant diseases.

Keywords: cancer; ribosome; ribosomopathies; translational fidelity.

Figure 1

Overview of ribosome biogenesis and the steps affected in ribosomopathies. The eukaryotic ribosome assembly process begins in the nucleolus, a sub-compartment of the nucleus that is organized around ribosomal DNA (rDNA) transcription units. Three of the four main ribosomal RNA (rRNA) molecules are transcribed in the nucleolus as precursor rRNA by RNA polymerase I, with the last rRNA molecule being transcribed in the nucleoplasm by RNA polymerase III. These pre-rRNAs undergo extensive structural modifications before becoming the final 18S, 25S, 5.8S, and 5S rRNAs. Ribosomal protein mRNAs are transcribed by RNA polymerase II in the nucleoplasm, translated into proteins in the cytoplasm, after which they are transported back to the nucleolus to participate in additional processing steps. These steps comprise the formation of numerous assembly intermediates, including a 90S pre-ribosome that begins to fold and further associate with ribosomal proteins, cleavage steps resulting in 43S and 66S pre-ribosomal particles, and their transport from the nucleolus into the nucleus and subsequently the cytoplasm for final rRNA processing and protein assembly events. Both subunits are exported into the cytoplasm with a complement of non-ribosomal factors, some of which facilitate export while others prevent the premature interaction of the ribosomal subunits. These factors must be released in the cytoplasm and shuttled back to the nucleus for subsequent rounds of maturation and export. After this recycling step, which is frequently coupled to final structural and functional quality controls of the assembled subunits, mature large 60S and small 40S subunits can interact to form translationally active 80S ribosomes. For simplicity, trans-acting biogenesis factors are referred to as assembly/processing factors, and can include ATP/GTPases, helicases, nucleases, kinases, small nucleolar RNAs (snoRNAs), chaperones, and protein co-factors. The biogenesis steps affected in ribosomopathies are marked with red arrows. Abbreviations: ER: endoplasmic reticulum; pol: polymerase; RP: ribosomal protein; mito-ribosomes: mitochondrial ribosomes.

Figure 2

Overview of the most common mutations and associated cancer risks in congenital ribosomopathies. The genes that are mutated or deleted in Diamond Blackfan anemia (DBA), dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH) and Shwachman–Diamond Syndrome (SDS) are indicated in the lightly shaded inner circles. The reported percentages indicate the fraction of patients with that ribosomopathy that presents a genetic defect in the corresponding gene. When the exact incidence of the defects are unknown, only the gene name is indicated. The outer, darker circles report the cancer types that occur at a significantly higher incidence in the shown ribosomopathy as compared to the healthy population. The size of the circles and the number reported below each cancer type represents the observed over expected (O/E) ratio and quantifies the risk increase for that particular cancer type in each ribosomopathy. Below the circle of each ribosomopathy, the overall cancer risk (O/E ratio) is reported.

Figure 3

A model of the cellular transition from hypo- to hyperproliferation in ribosome-mutant diseases. Ribosomal defects alter the cellular translational landscape, promoting a protein expression profile that favors growth-promoting and disfavors tumor-suppressing factors. Defects in the assembly and/or function of ribosomes also leads to increased cellular stress and production of reactive oxygen species (ROS), which inhibits cellular proliferation and promotes DNA damage and higher mutagenesis. Over time, rescuing mutations arise that inhibit ROS production, thereby removing the block on cellular proliferation. This unleashes the cellular oncogenic potential, marking the beginning of the affected cell’s progression to transformation. RP: ribosomal protein.