CRL4-DCAF15 E3 泛素连接酶复合物被芳基磺酰胺分子胶靶向，导致新底物招募、泛素化和蛋白酶体降解。然而，DCAF15的生理功能仍不清楚。使用以领域为中心的遗传筛查方法，我们揭示了 DCAF15 是一种急性髓系白血病 (AML) 偏倚依赖性。 DCAF15 的缺失会通过复制叉完整性受损和随后的 DNA 损伤累积来抑制 AML。因此，DCAF15 缺失使 AML 对复制应激诱导疗法敏感。从机制上讲，我们发现 DCAF15 直接与粘连蛋白复合物的 SMC1A 蛋白相互作用，并使粘连蛋白调节因子 PDS5A 和 CDCA5 不稳定。 PDS5A 和 CDCA5 去除的缺失会阻止染色质上的粘连蛋白乙酰化，从而导致不受控制的染色质环挤出、DNA 复制缺陷和细胞凋亡。总的来说，我们的研究结果揭示了 DCAF15 通过翻译后控制粘连蛋白动力学维持 AML 增殖的内源性细胞自主功能。© 2024。作者。

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).