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Somatic genetic rescue of a germline ribosome assembly defect
- Source :
- Nature Communications, Nature Communications, Nature Publishing Group, 2021, 12 (1), ⟨10.1038/s41467-021-24999-5⟩, Nature Communications, 2021, 12 (1), ⟨10.1038/s41467-021-24999-5⟩, Nature communications, 12(1):5044. Nature Publishing Group, Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021)
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- 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.<br />Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.
- Subjects :
- Somatic cell
[SDV]Life Sciences [q-bio]
General Physics and Astronomy
[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Germline
631/208/737
692/699/1541
Ribosome assembly
13/1
0302 clinical medicine
hemic and lymphatic diseases
38/22
Dictyostelium
Eukaryotic Initiation Factors
Child
Cells, Cultured
Biological Phenomena
Genetics
0303 health sciences
Multidisciplinary
631/208/514/2254
article
[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Ribosome Subunits, Large, Eukaryotic
Ribosome
Shwachman-Diamond Syndrome
3. Good health
[SDV] Life Sciences [q-bio]
64/24
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology
030220 oncology & carcinogenesis
Child, Preschool
Drosophila
Haematological diseases
Protein Binding
Adult
congenital, hereditary, and neonatal diseases and abnormalities
Adolescent
Science
45/23
Saccharomyces cerevisiae
Biology
Molecular Dynamics Simulation
General Biochemistry, Genetics and Molecular Biology
82/80
03 medical and health sciences
Young Adult
Germline mutation
Animals
Humans
Gene
Ribonucleoprotein, U5 Small Nuclear
030304 developmental biology
Sequence Homology, Amino Acid
Eukaryotic Large Ribosomal Subunit
Point mutation
Infant
Proteins
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
General Chemistry
SBDS
96/44
Peptide Elongation Factors
Germ Cells
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Protein Biosynthesis
Mutation
Next-generation sequencing
631/337/574/1789
Ribosomes
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications, Nature Communications, Nature Publishing Group, 2021, 12 (1), ⟨10.1038/s41467-021-24999-5⟩, Nature Communications, 2021, 12 (1), ⟨10.1038/s41467-021-24999-5⟩, Nature communications, 12(1):5044. Nature Publishing Group, Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021)
- Accession number :
- edsair.doi.dedup.....64a0a029184f8fcc8469d2a5ac081086