DCAF15 control of cohesin dynamics sustains acute myeloid leukemia

Grant P. Grothusen, Renxu Chang, Zhendong Cao, Nan Zhou, Monika Mittal, Arindam Datta, Phillip Wulfridge, Thomas Beer, Baiyun Wang, Ning Zheng, Hsin-Yao Tang, Kavitha Sarma, Roger A. Greenberg, Junwei Shi and Luca Busino ()
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Grant P. Grothusen: University of Pennsylvania
Renxu Chang: University of Pennsylvania
Zhendong Cao: University of Pennsylvania
Nan Zhou: University of Pennsylvania
Monika Mittal: University of Pennsylvania
Arindam Datta: University of Pennsylvania
Phillip Wulfridge: The Wistar Institute
Thomas Beer: The Wistar Institute
Baiyun Wang: University of Washington
Ning Zheng: University of Washington
Hsin-Yao Tang: The Wistar Institute
Kavitha Sarma: The Wistar Institute
Roger A. Greenberg: University of Pennsylvania
Junwei Shi: University of Pennsylvania
Luca Busino: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49882-x

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