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dc.contributor.authorKhan, OM
dc.contributor.authorAlmagro, J
dc.contributor.authorNelson, JK
dc.contributor.authorHorswell, S
dc.contributor.authorEncheva, V
dc.contributor.authorKeyan, KS
dc.contributor.authorClurman, BE
dc.contributor.authorSnijders, AP
dc.contributor.authorBehrens, A
dc.date.accessioned2021-06-11T12:58:16Z
dc.date.available2021-06-11T12:58:16Z
dc.date.issued2021-04-06
dc.identifier.citationNature communications, 2021, 12 (1), pp. 2043 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4630
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-021-22319-5
dc.description.abstractThe tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCF FBW7 -mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCF FBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.
dc.formatElectronic
dc.format.extent2043 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHCT116 Cells
dc.subjectHumans
dc.subjectProteasome Endopeptidase Complex
dc.subjectUbiquitin-Conjugating Enzymes
dc.subjectUbiquitin-Protein Ligases
dc.subjectLysine
dc.subjectCarrier Proteins
dc.subjectRNA, Small Interfering
dc.subjectProtein Processing, Post-Translational
dc.subjectProtein Binding
dc.subjectSubstrate Specificity
dc.subjectDrug Resistance, Neoplasm
dc.subjectUbiquitination
dc.subjectBiocatalysis
dc.subjectProtein Stability
dc.subjectHEK293 Cells
dc.subjectProteolysis
dc.subjectMyeloid Cell Leukemia Sequence 1 Protein
dc.subjectF-Box-WD Repeat-Containing Protein 7
dc.titleProteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12.
dc.typeJournal Article
dcterms.dateAccepted2021-03-03
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-021-22319-5
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-04-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.publication-statusPublished
pubs.volume12
pubs.embargo.termsNot known
dc.contributor.icrauthorBehrens, Axelen


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