Becht Dustin C, Selvam Karthik, Lachance Catherine, Côté Valérie, Li Kuai, Nguyen Minh Chau, Pareek Akshay, Shi Xiaobing, Wen Hong, Blanco M Andres, Côté Jacques, Kutateladze Tatiana G
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
St-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Québec City, Québec, Canada.
Nat Struct Mol Biol. 2025 Apr;32(4):709-718. doi: 10.1038/s41594-024-01455-8. Epub 2025 Jan 10.
The epigenetic cofactor ENL (eleven-nineteen-leukemia) and the acetyltransferase MOZ (monocytic leukemia zinc finger) have vital roles in transcriptional regulation and are implicated in aggressive forms of leukemia. Here, we describe the mechanistic basis for the intertwined association of ENL and MOZ. Genomic analysis shows that ENL and MOZ co-occupy active promoters and that MOZ recruits ENL to its gene targets. Structural studies reveal a multivalent assembly of ENL at the intrinsically disordered region (IDR) of MOZ. While the extraterminal (ET) domain of ENL recognizes the canonical ET-binding motif in IDR, the YEATS domains of ENL and homologous AF9 bind to a set of acetylation sites in the MOZ IDR that are generated by the acetyltransferase CBP (CREB-binding protein). Our findings suggest a multifaceted acetylation-dependent and independent coupling of ENL, MOZ and CBP/p300, which may contribute to leukemogenic activities of the ENL-MOZ assembly and chromosomal translocations of ENL, MOZ and CBP/p300.
表观遗传辅因子ENL（11-19白血病）和乙酰转移酶MOZ（单核细胞白血病锌指蛋白）在转录调控中发挥着重要作用，并与侵袭性白血病形式有关。在此，我们描述了ENL和MOZ相互关联的机制基础。基因组分析表明，ENL和MOZ共同占据活跃启动子，且MOZ将ENL招募至其基因靶点。结构研究揭示了ENL在MOZ的内在无序区域（IDR）形成多价组装。虽然ENL的末端外（ET）结构域识别IDR中的典型ET结合基序，但ENL的YEATS结构域和同源的AF9结合到MOZ IDR中由乙酰转移酶CBP（环磷腺苷效应元件结合蛋白）产生的一组乙酰化位点。我们的研究结果表明，ENL、MOZ和CBP/p300存在多方面的乙酰化依赖性和非依赖性偶联，这可能有助于ENL-MOZ组装的致白血病活性以及ENL、MOZ和CBP/p300的染色体易位。
