DCAF15 control of cohesin dynamics sustains acute myeloid leukemia.

Autor: Grothusen GP; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Chang R; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Cao Z; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Zhou N; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Mittal M; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Datta A; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wulfridge P; Ellen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia, PA, USA., Beer T; Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, USA., Wang B; Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, USA., Zheng N; Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, USA., Tang HY; Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, USA., Sarma K; Ellen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia, PA, USA., Greenberg RA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Shi J; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Busino L; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. businol@upenn.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 03; Vol. 15 (1), pp. 5604. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1038/s41467-024-49882-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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