Repository logo
 

Somatic genetic rescue of a germline ribosome assembly defect.

Simple item page
cam.issuedOnline2021-08-19
dc.contributor.authorTan, Shengjiang
dc.contributor.authorKermasson, Laëtitia
dc.contributor.authorHilcenko, Christine
dc.contributor.authorKargas, Vasileios
dc.contributor.authorTraynor, David
dc.contributor.authorBoukerrou, Ahmed Z
dc.contributor.authorEscudero-Urquijo, Norberto
dc.contributor.authorFaille, Alexandre
dc.contributor.authorBertrand, Alexis
dc.contributor.authorRossmann, Maxim
dc.contributor.authorGoyenechea, Beatriz
dc.contributor.authorJin, Li
dc.contributor.authorMoreil, Jonathan
dc.contributor.authorAlibeu, Olivier
dc.contributor.authorBeaupain, Blandine
dc.contributor.authorBôle-Feysot, Christine
dc.contributor.authorFumagalli, Stefano
dc.contributor.authorKaltenbach, Sophie
dc.contributor.authorMartignoles, Jean-Alain
dc.contributor.authorMasson, Cécile
dc.contributor.authorNitschké, Patrick
dc.contributor.authorParisot, Mélanie
dc.contributor.authorPouliet, Aurore
dc.contributor.authorRadford-Weiss, Isabelle
dc.contributor.authorTores, Frédéric
dc.contributor.authorde Villartay, Jean-Pierre
dc.contributor.authorZarhrate, Mohammed
dc.contributor.authorKoh, Ai Ling
dc.contributor.authorPhua, Kong Boo
dc.contributor.authorReversade, Bruno
dc.contributor.authorBond, Peter J
dc.contributor.authorBellanné-Chantelot, Christine
dc.contributor.authorCallebaut, Isabelle
dc.contributor.authorDelhommeau, François
dc.contributor.authorDonadieu, Jean
dc.contributor.authorWarren, Alan J
dc.contributor.authorRevy, Patrick
dc.contributor.orcidEscudero-Urquijo, Norberto [0000-0002-8201-5884]
dc.contributor.orcidParisot, Mélanie [0000-0003-4312-2035]
dc.contributor.orcidReversade, Bruno [0000-0002-4070-7997]
dc.contributor.orcidBond, Peter J [0000-0003-2900-098X]
dc.contributor.orcidBellanné-Chantelot, Christine [0000-0001-8415-6771]
dc.contributor.orcidWarren, Alan J [0000-0001-9277-4553]
dc.contributor.orcidRevy, Patrick [0000-0003-0758-8022]
dc.date.accessioned2022-06-29T19:45:03Z
dc.date.available2022-06-29T19:45:03Z
dc.date.issued2021-08-19
dc.date.submitted2020-10-20
dc.date.updated2022-06-29T19:45:03Z
dc.description.abstractIndirect 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.
dc.description.sponsorshipBlood 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”.
dc.identifier.doi10.17863/CAM.85908
dc.identifier.eissn2041-1723
dc.identifier.issn2041-1723
dc.identifier.others41467-021-24999-5
dc.identifier.other24999
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338495
dc.languageen
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41467-021-24999-5
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAnimals
dc.subjectBiological Phenomena
dc.subjectCells, Cultured
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectDictyostelium
dc.subjectDrosophila
dc.subjectEukaryotic Initiation Factors
dc.subjectGerm Cells
dc.subjectHumans
dc.subjectInfant
dc.subjectMolecular Dynamics Simulation
dc.subjectMutation
dc.subjectPeptide Elongation Factors
dc.subjectProtein Binding
dc.subjectProtein Biosynthesis
dc.subjectProteins
dc.subjectRibonucleoprotein, U5 Small Nuclear
dc.subjectRibosome Subunits, Large, Eukaryotic
dc.subjectRibosomes
dc.subjectSaccharomyces cerevisiae
dc.subjectSequence Homology, Amino Acid
dc.subjectShwachman-Diamond Syndrome
dc.subjectYoung Adult
dc.titleSomatic genetic rescue of a germline ribosome assembly defect.
dc.typeArticle
dcterms.dateAccepted2021-07-12
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume12
pubs.funder-project-idBloodwise (15035)
pubs.funder-project-idMRC (MR/T012412/1)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
pubs.funder-project-idLeukaemia & Lymphoma Research (11027)
pubs.funder-project-idLeukaemia & Lymphoma Research (12048)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-021-24999-5

Files

Original bundle
Now showing 1 - 5 of 5
Thumbnail Image
Name:
41467_2021_24999_MOESM1_ESM.pdf
Size:
3.59 MB
Format:
Adobe Portable Document Format
Description:
Published version
Licence
http://creativecommons.org/licenses/by/4.0/
Download
Thumbnail Image
Name:
41467_2021_24999_MOESM6_ESM.pdf
Size:
2.27 MB
Format:
Adobe Portable Document Format
Description:
Published version
Licence
http://creativecommons.org/licenses/by/4.0/
Download
No Thumbnail Available
Name:
additional-files.zip
Size:
21.52 MB
Format:
ZIP file
Description:
Supporting information
Licence
http://creativecommons.org/licenses/by/4.0/
Download
No Thumbnail Available
Name:
41467_2021_Article_24999_nlm.xml
Size:
173.5 KB
Format:
Extensible Markup Language
Description:
Bibliographic metadata
Licence
http://creativecommons.org/licenses/by/4.0/
Download
Thumbnail Image
Name:
41467_2021_Article_24999.pdf
Size:
3.66 MB
Format:
Adobe Portable Document Format
Description:
Published version
Licence
http://creativecommons.org/licenses/by/4.0/
Download

Collections

Jisc Publications Router