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dc.contributor.authorCalamita, P
dc.contributor.authorMiluzio, A
dc.contributor.authorRusso, A
dc.contributor.authorPesce, E
dc.contributor.authorRicciardi, S
dc.contributor.authorKhanim, F
dc.contributor.authorCheroni, C
dc.contributor.authorAlfieri, R
dc.contributor.authorMancino, M
dc.contributor.authorGorrini, C
dc.contributor.authorRossetti, G
dc.contributor.authorPeluso, I
dc.contributor.authorPagani, M
dc.contributor.authorMedina, DL
dc.contributor.authorRommens, J
dc.contributor.authorBiffo, S
dc.date.accessioned2020-09-30T12:57:47Z
dc.date.issued2017-01-05
dc.identifier.citationPLoS genetics, 2017, 13 (1), pp. e1006552 - ?
dc.identifier.issn1553-7390
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4101
dc.identifier.eissn1553-7404
dc.identifier.doi10.1371/journal.pgen.1006552
dc.description.abstractRibosomopathies are a family of inherited disorders caused by mutations in genes necessary for ribosomal function. Shwachman-Diamond Bodian Syndrome (SDS) is an autosomal recessive disease caused, in most patients, by mutations of the SBDS gene. SBDS is a protein required for the maturation of 60S ribosomes. SDS patients present exocrine pancreatic insufficiency, neutropenia, chronic infections, and skeletal abnormalities. Later in life, patients are prone to myelodisplastic syndrome and acute myeloid leukemia (AML). It is unknown why patients develop AML and which cellular alterations are directly due to the loss of the SBDS protein. Here we derived mouse embryonic fibroblast lines from an SbdsR126T/R126T mouse model. After their immortalization, we reconstituted them by adding wild type Sbds. We then performed a comprehensive analysis of cellular functions including colony formation, translational and transcriptional RNA-seq, stress and drug sensitivity. We show that: 1. Mutant Sbds causes a reduction in cellular clonogenic capability and oncogene-induced transformation. 2. Mutant Sbds causes a marked increase in immature 60S subunits, limited impact on mRNA specific initiation of translation, but reduced global protein synthesis capability. 3. Chronic loss of SBDS activity leads to a rewiring of gene expression with reduced ribosomal capability, but increased lysosomal and catabolic activity. 4. Consistently with the gene signature, we found that SBDS loss causes a reduction in ATP and lactate levels, and increased susceptibility to DNA damage. Combining our data, we conclude that a cell-specific fragile phenotype occurs when SBDS protein drops below a threshold level, and propose a new interpretation of the disease.
dc.formatElectronic-eCollection
dc.format.extente1006552 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line
dc.subjectFibroblasts
dc.subjectAnimals
dc.subjectMice
dc.subjectCell Transformation, Neoplastic
dc.subjectDNA Damage
dc.subjectLactic Acid
dc.subjectProteins
dc.subjectRNA, Messenger
dc.subjectAdenosine Triphosphate
dc.subjectHomeostasis
dc.subjectPhenotype
dc.subjectRibosome Subunits, Large, Eukaryotic
dc.titleSBDS-Deficient Cells Have an Altered Homeostatic Equilibrium due to Translational Inefficiency Which Explains their Reduced Fitness and Provides a Logical Framework for Intervention.
dc.typeJournal Article
dcterms.dateAccepted2016-12-24
rioxxterms.versionofrecord10.1371/journal.pgen.1006552
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-01-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfPLoS genetics
pubs.issue1
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.publication-statusPublished
pubs.volume13en_US
pubs.embargo.termsNo embargo
icr.researchteamTarget Evaluation and Molecular Therapeuticsen_US
dc.contributor.icrauthorGorrini, Chiaraen


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