Susan Baserga

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Jayjit Majumdar

University of Kalyani

Stephen Mackessy

University of Northern Colorado

Julie T Daniels

University College London

Gary Rubin

University College London

Soon -Guan Tan

UPM - Universiti Putra Malaysia

che pillay

University of KwaZulu-Natal

Paul H Artes

Plymouth University

Jean-Luc Legras

Institut National de la Recherche Agronomique

Rosna Mat Taha

University of Malaya, Malaysia

Alejandra Alvarez

Pontificia Universidad Catolica de Chile

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Ribosomopathies: Old Concepts, New Controversies

Trends in Genetics, Oct 1, 2019

Ribosomopathies are a diverse subset of diseases caused by reduced expression of, or mutations in... more 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. Ribosomopathies are a diverse subset of largely developmental disorders that result from aberrant ribosome production. Ribosome synthesis is an essential and energy-intensive cellular process that requires the coordination of all three RNA polymerases, ~200 accessory factors, and 80 ribosomal proteins (r-proteins) to process and assemble the mature ribosomal RNAs (rRNAs) . In humans, the bulk of ribosome biogenesis initiates in the nucleolus with transcription of the 47S pre-rRNA from ribosomal DNA (rDNA) loci by RNA polymerase I (RNAPI). Following transcription, the pre-rRNA is processed by a series of endo-and exonucleolytic steps to yield three of the four mature rRNAs (18S, 5.8S, and 28S) . The rRNAs are also modified by box C/D and H/ACA small nucleolar ribonucleoproteins (snoRNPs), and assembled with r-proteins and the fourth rRNA (5S), transcribed by RNA polymerase III from an extranucleolar locus . Together, these steps yield the mature small subunit (SSU, 40S) and the large subunit (LSU, 60S) of the ribosome that come together in the cytoplasm to translate mRNA into proteins. When it was first discovered that difficulties in making ribosomes could lead to the bone marrow failure syndrome, Diamond-Blackfan anemia (DBA) [3], it was unclear how a defect in the ubiquitous process of making ribosomes could lead to a tissue-specific disorder. Since then, new ribosomopathies have been identified, each with tissue-specific manifestations. There have been several recent comprehensive reviews on ribosomopathies [4-8], and we therefore discuss only the new and controversial aspects of their pathogenesis. First, we highlight new ribosomopathies based on which step of ribosome biogenesis is affected. Second, we discuss the tissue-specific manifestations of the ribosomopathies, and present a hypothesis defining how defects in the global process of making ribosomes may only affect some tissues. Finally, we pose key open questions and discuss current controversies surrounding ribosomopathies, such as (i) do specialized ribosomes influence the pathogenesis of ribosomopathies? (ii) How can defects in cell growth cause cancer? (iii) Are aging and neurodegenerative diseases also ribosomopathies? Although there is currently no single unifying principle that explains the pathogenesis of all known ribosomopathies, substantial progress has been made in recognizing Ribosomopathies are disorders of making ribosomes that manifest in afflicted humans with tissue-specificity. Several new ribosomopathies have recently been discovered, helping to reveal the link between ribosome biogenesis and human development. The specialized ribosomes hypothesis states that the tissue-specific defects of ribosomopathies are due to ribosome heterogeneity caused by changes in ribosomal protein composition or modification, rRNA composition or modification, or accessory protein binding. The ribosome concentration hypothesis states that the tissue-specific defects of ribosomopathies are due to changes in mRNA translation as a consequence of reduced ribosome number. Dysregulation of nucleolar activity is associated with aging and neurodegeneration, suggesting that these disorders may perhaps also be ribosomopathies.

Susan Baserga

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