Abstract
Mutations that target the ubiquitous process of ribosome assembly paradoxically cause diverse tissue-specific disorders (ribosomopathies) that are often associated with an increased risk of cancer. Ribosomes are the essential macromolecular machines that read the genetic code in all cells in all kingdoms of life. Following pre-assembly in the nucleus, precursors of the large 60S and small 40S ribosomal subunits are exported to the cytoplasm where the final steps in maturation are completed. Here, I review the recent insights into the conserved mechanisms of ribosome assembly that have come from functional characterisation of the genes mutated in human ribosomopathies. In particular, recent advances in cryo-electron microscopy, coupled with genetic, biochemical and prior structural data, have revealed that the SBDS protein that is deficient in the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome couples the final step in cytoplasmic 60S ribosomal subunit maturation to a quality control assessment of the structural and functional integrity of the nascent particle. Thus, study of this fascinating disorder is providing remarkable insights into how the large ribosomal subunit is functionally activated in the cytoplasm to enter the actively translating pool of ribosomes.
Highlights
Shwachman-Diamond syndrome (SDS, OMIM #260400) is a fascinating autosomal recessive disorder associated with bone marrow failure and an increased risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)
This conclusion is strongly supported by the identification of mutations in the 60S ribosomal subunit assembly factor DNAJC21 in SDS patients who are negative for mutations in the SBDS gene
The diverse phenotypes associated with the human ribosomopathies raise a key conundrum: how do mutations that perturb the ubiquitous process of ribosome assembly cause such tissue specific defects? Consistent with a fundamental conserved role for the SBDS protein in 60S subunit maturation and ribosomal subunit joining, global translation is reduced in Sdo1-deficient yeast cells (Menne et al, 2007), in mouse embryonic fibroblasts expressing the disease-related Sbds-R126T missense mutation (Calamita et al, 2017) and in human kidney 293 cells depleted of SBDS by siRNA (Ball et al, 2009)
Summary
Shwachman-Diamond syndrome (SDS, OMIM #260400) is a fascinating autosomal recessive disorder associated with bone marrow failure and an increased risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Among young adults (18e40 years old) transplanted for MDS who were enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR) repository between 2005 and 14, 4% were discovered to have germline compound heterozygous mutations in the SBDS gene (Lindsley et al, 2017) with concurrent somatic biallelic loss-offunction TP53 variants. These SDS patients, who were mostly undiagnosed prior to transplant, had a remarkably poor prognosis (median survival of 1.2 years). We need to harness new mechanistic insights to develop novel therapeutics that will improve the outcomes for SDS patients and their families
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
