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| Status |
Public on May 22, 2024 |
| Title |
CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.
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| Overall design |
Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis for total-SMC3 and acetyl-SMC3 in HEL human AML cell line without or with genetic knockout of DCAF15.
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| Contributor(s) |
Grothusen GP, Zhou N, Busino L |
| Citation(s) |
38961054 |
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| Submission date |
Aug 23, 2023 |
| Last update date |
Aug 21, 2024 |
| Contact name |
Luca Busino |
| E-mail(s) |
businol@upenn.edu
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| Phone |
215-746-2569
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| Organization name |
University of Pennsylvania
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| Department |
Cancer Biology
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| Lab |
Luca Busino Laboratory
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| Street address |
421 Curie Boulevard
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| City |
Philadelphia |
| State/province |
Pennsylvania |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
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| Samples (5)
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| GSM7731248 |
HEL cells, LRCherry2.1-sgROSA26(Control), Input |
| GSM7731249 |
HEL cells, LRCherry2.1-sgROSA26(Control), total-SMC3, ChIP |
| GSM7731250 |
HEL cells, LRCherry2.1-sgROSA26(Control), acetyl-SMC3, ChIP |
| GSM7731251 |
HEL cells, LRCherry2.1-sgDCAF15#2, total-SMC3, ChIP |
| GSM7731252 |
HEL cells, LRCherry2.1-sgDCAF15#2, acetyl-SMC3, ChIP |
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| This SubSeries is part of SuperSeries: |
| GSE241581 |
DCAF15 control of cohesin dynamics sustains acute myeloid leukemia |
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| Relations |
| BioProject |
PRJNA1008730 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE241579_RAW.tar |
726.0 Mb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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