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| Status |
Public on Mar 30, 2022 |
| Title |
Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
D283MED cell lines conditionally expressing KBTBD4 WT, R313PRR or P311PR
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| Contributor(s) |
Chen Z, Ioris RM, Bullock AN, D'Angiolella V |
| Citation(s) |
35379950 |
| Submission date |
Feb 22, 2022 |
| Last update date |
Jun 13, 2022 |
| Contact name |
Vincenzo D'Angiolella |
| E-mail(s) |
vincenzo.dangiolella@oncology.ox.ac.uk
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| Organization name |
University of Oxford
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| Street address |
Old Road Campus Research Building, Old Road Campus, Off, Roosevelt Dr
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| City |
Oxford |
| State/province |
Oxfordshire |
| ZIP/Postal code |
OX3 7DQ |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (24)
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| GSM5911411 |
D283MED cell lines conditionally expressing KBTBD4 WT - Replicate 1 |
| GSM5911412 |
D283MED cell lines conditionally expressing KBTBD4 WT - Replicate 2 |
| GSM5911413 |
D283MED cell lines conditionally expressing KBTBD4 WT - Replicate 3 |
| GSM5911414 |
D283MED cell lines conditionally expressing KBTBD4 WT - Replicate 4 |
| GSM5911415 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR - Replicate 1 |
| GSM5911416 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR - Replicate 2 |
| GSM5911417 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR - Replicate 3 |
| GSM5911418 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR - Replicate 4 |
| GSM5911419 |
D283MED cell lines conditionally expressing KBTBD4 R311PR - Replicate 1 |
| GSM5911420 |
D283MED cell lines conditionally expressing KBTBD4 R311PR - Replicate 2 |
| GSM5911421 |
D283MED cell lines conditionally expressing KBTBD4 R311PR - Replicate 3 |
| GSM5911422 |
D283MED cell lines conditionally expressing KBTBD4 R311PR - Replicate 4 |
| GSM5911423 |
D283MED cell lines conditionally expressing KBTBD4 WT, doxycycline treated, Replicate 1 |
| GSM5911424 |
D283MED cell lines conditionally expressing KBTBD4 WT, doxycycline treated, Replicate 2 |
| GSM5911425 |
D283MED cell lines conditionally expressing KBTBD4 WT, doxycycline treated, Replicate 3 |
| GSM5911426 |
D283MED cell lines conditionally expressing KBTBD4 WT, doxycycline treated, Replicate 4 |
| GSM5911427 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR, doxycycline treated, Replicate 1 |
| GSM5911428 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR, doxycycline treated, Replicate 2 |
| GSM5911429 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR, doxycycline treated, Replicate 3 |
| GSM5911430 |
D283MED cell lines conditionally expressing KBTBD4 R313PRR, doxycycline treated, Replicate 4 |
| GSM5911431 |
D283MED cell lines conditionally expressing KBTBD4 R311PR, doxycycline treated, Replicate 1 |
| GSM5911432 |
D283MED cell lines conditionally expressing KBTBD4 R311PR, doxycycline treated, Replicate 2 |
| GSM5911433 |
D283MED cell lines conditionally expressing KBTBD4 R311PR, doxycycline treated, Replicate 3 |
| GSM5911434 |
D283MED cell lines conditionally expressing KBTBD4 R311PR, doxycycline treated, Replicate 4 |
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| Relations |
| BioProject |
PRJNA809413 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE197240_genes.readcount.xls.gz |
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(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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