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| Status |
Public on May 17, 2024 |
| Title |
ChIP-seq of BRD4 of HCT116 cells treated with MZ1 or PDD00017273 |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Targeted protein degradation is a groundbreaking modality in drug discovery ; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related hard-to-degrade targets BRD2/3 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC–CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.
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| Overall design |
BRD4 binding profiles in HCT116 cells treated with MZ1 and PDD00017273 were generated by ChIP-sequencing using illumina NextSeq 2000
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| Contributor(s) |
Ohtake F, Hattori N |
| Citation missing |
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| Submission date |
Apr 01, 2024 |
| Last update date |
May 18, 2024 |
| Contact name |
Naoko Hattori |
| E-mail(s) |
naokohattori0514@gmail.com
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| Organization name |
Hoshi University
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| Department |
Department of Epigenomics
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| Street address |
2-4-41 Ebara, Shinagawa-ku
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| City |
Tokyo |
| ZIP/Postal code |
142-8501 |
| Country |
Japan |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1094952 |
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