Journal Article

Ribosomopathies

Green, Rachel, Mills, Eric W.

2017

Overview

Ribosomopathies are t issuespecific disorders that result from mutations in ribosomal proteins or ribosome biogenesis factors. Such disorders include Diamond-Blackfan anemia, isolated congenital asplenia, and Treacher Collins syndrome. Mills and Green review the underlying mechanisms of tissue-specific defects in these and related disorders. Because ribosomes are central to all cellular life, it is puzzling why mutations in components of the ribosome disproportionately affect certain tissues. The authors suggest that ribosome homeostasis is an overarching and simplifying principle that governs the sensitivity of specific cells and tissue types to mutation in components of the translational machinery. Science , this issue p. eaan2755 Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features. We discuss ribosome homeostasis as an overarching principle that governs the sensitivity of specific cells and tissue types to ribosomal protein mutations. Mathematical models and experimental insights rationalize how even subtle shifts in the availability of ribosomes, such as those created by ribosome haploinsufficiency, can drive messenger RNA–specific effects on protein expression. We discuss recently identified roles played by ribosome rescue and recycling factors in regulating ribosome homeostasis.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Anemia / Anemia, Diamond-Blackfan - genetics / Anemia, Diamond-Blackfan - metabolism / Animal models / Apoptosis / Asplenia / Biosynthesis / Bone marrow / Cell activation / Cell cycle / Cell Cycle Checkpoints / Composition / Defects / Disorders / Evolution / Footprinting / Gene expression / Haploinsufficiency / Heterogeneity / Homeostasis / Humans / Hypotheses / Mathematical models / Models, Biological / Molecular modelling / Mutation / Organ Specificity / p53 Protein / Perturbation / Protein Biosynthesis / Protein synthesis / Proteins / REVIEW SUMMARY / Ribonucleic acid / Ribosomal DNA / Ribosomal proteins / Ribosomal Proteins - genetics / Ribosomes / Ribosomes - genetics / Ribosomes - metabolism / RNA / Sensitivity / Signal transduction / Tissues / Transfer RNA / Translation / Tumor Suppressor Protein p53 - metabolism