Somatic genetic rescue of a germline ribosome assembly defect.
Creators: name: Tan, Shengjiang
name: Kermasson, Laëtitia
name: Hilcenko, Christine
name: Kargas, Vasileios
name: Traynor, David
name: Boukerrou, Ahmed Zakaria
name: Escudero-Urquijo, Norberto
name: Faille, Alexandre
name: Bertrand, Alexis
name: Rossmann, Maxim
name: Goyenechea, Beatriz
name: Jin, Li
name: Moreil, Jonathan
name: Alibeu, Olivier
name: Beaupain, Blandine
name: Bôle-Feysot, Christine
name: Fumagalli, Stefano
name: Kaltenbach, Sophie
name: Martignoles, Jean-Alain
name: Masson, Cécile
name: Nitschké, Patrick
name: Parisot, Mélanie
name: Pouliet, Aurore
name: Radford-Weiss, Isabelle
name: Tores, Frédéric
name: De Villartay, Jean-Pierre
name: Zarhrate, Mohammed
name: Koh, Ai Ling
name: Phua, Kong Boo
name: Reversade, Bruno
name: Bond, Peter J
name: Bellanné-Chantelot, Christine
name: Callebaut, Isabelle
name: Delhommeau, François
name: Donadieu, Jean
name: Warren, Alan
name: Revy, Patrick
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Germ Cells
Cells, Cultured
Ribosomes
Animals
Humans
Drosophila
Dictyostelium
Saccharomyces cerevisiae
Proteins
Ribonucleoprotein, U5 Small Nuclear
Peptide Elongation Factors
Eukaryotic Initiation Factors
Biological Phenomena
Protein Biosynthesis
Protein Binding
Sequence Homology, Amino Acid
Mutation
Adolescent
Adult
Child
Child, Preschool
Infant
Ribosome Subunits, Large, Eukaryotic
Young Adult
Molecular Dynamics Simulation
Shwachman-Diamond Syndrome

description: Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.
description: Blood Cancer UK, UK Medical Research Council, Kay Kendall Leukaemia Fund, a Wellcome Trust strategic award to the Cambridge Institute for Medical Research, a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, the Connor Wright Project, the Cambridge National Institute for Health Research Biomedical Research Centre and the European Cooperation in Science and Technology (COST) Action CA18233 “European Network for Innovative Diagnosis and treatment of Chronic Neutropenias, EuNet INNOCHRON”.