Regulation Of Acute Myeloid Leukemia Cell Proliferation By E3 Ubiquitin Ligase DCAF15 Control Of Cohesin Dynamics

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell and Molecular Biology
Discipline
Biology
Biology
Genetics and Genomics
Subject
AML
cancer
cohesin
DCAF15
leukemia
ubiquitin
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2023
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Grothusen, Grant, Peter
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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.

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Busino, Luca
Date of degree
2023
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