PXD031683

PXD031683 is an original dataset announced via ProteomeXchange.

Title	Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradationDisease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation
Description	E3 ubiquitin ligases of the Cullin RING Ligase (CRL) family assemble into multiprotein complexes to diversify substrate adaptors and ensure selectivity in substrate engagement for degradation. Here we show a novel mechanism whereby mutations in substrate adaptors can drive neo-substrate degradation in cancer. KBTBD4 is a CRL3 substrate adaptor harbouring recurrent indel mutations in a subset of non-WNT/non-SHH medulloblastomas. We show that these mutations, arising in the substrate recognition domain of KBTBD4, promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. We observe that this neomorphic activity of KBTBD4 mutants induces changes in epigenetic markers and significant alterations in transcription, diverting normal cellular programmes towards increased stemness. These results highlight mutation-driven neomorphic E3 ligase activity as a previously unrecognised mechanism in tumorigenesis, with implications for medulloblastoma pathogenesis and treatment.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:36:35.268.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD031683
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	iolanda Vendrell
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-15 01:45:42	ID requested
1	2022-10-14 12:25:20	announced
⏵ 2	2023-11-14 07:36:36	announced	2023-11-14: Updated project metadata.

10.6019/PXD031683;

Chen Z, Ioris RM, Richardson S, Van Ess AN, Vendrell I, Kessler BM, Buffa FM, Busino L, Clifford SC, Bullock AN, D'Angiolella V, Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation. Cell Death Differ, 29(10):1955-1969(2022) [pubmed]

submitter keyword: Medulloblastoma, KBTBD4, ubiquitin, CoREST, Epigenetic remodelling

Vincenzo D'Angiolella
contact affiliation	Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
contact email	vincenzo.dangiolella@oncology.ox.ac.uk
lab head
iolanda Vendrell
contact affiliation	Target Discovery Institute, NDMRB
contact email	iolanda.vendrell@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031683
     1. Label: PRIDE project
     2. Name: Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradationDisease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation