A multivalent engagement of ENL with MOZ

  • Nat Struct Mol Biol. 2025 Apr;32(4):709-718. doi: 10.1038/s41594-024-01455-8.
Dustin C Becht  #  1 ,  Karthik Selvam  #  1 ,  Catherine Lachance  #  2 ,  Valérie Côté  2 ,  Kuai Li  3 ,  Minh Chau Nguyen  1 ,  Akshay Pareek  1 ,  Xiaobing Shi  3 ,  Hong Wen  3 ,  M Andres Blanco  4 ,  Jacques Côté  2 ,  Tatiana G Kutateladze  5
Affiliations
  • 1. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
  • 2. 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.
  • 3. Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
  • 4. Department of Biomedical Sciences, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA.
  • 5. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA. [email protected].
  • # Contributed equally.
PMID: 39794553 DOI: 10.1038/s41594-024-01455-8
Abstract

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.