2. Academic Validation
  3. MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

  • Nat Commun. 2023 Feb 8;14(1):697. doi: 10.1038/s41467-023-36368-5.
Dustin C Becht # 1,  Brianna J Klein # 1,  Akinori Kanai # 2,  Suk Min Jang # 3,  Khan L Cox 4,  Bing-Rui Zhou 5,  Sabrina K Phanor 6,  Yi Zhang 1,  Ruo-Wen Chen 4,  Christopher C Ebmeier 7,  Catherine Lachance 3,  Maxime Galloy 3,  Amelie Fradet-Turcotte 3,  Martha L Bulyk 6 8,  Yawen Bai 5,  Michael G Poirier 4,  Jacques Côté 9,  Akihiko Yokoyama 10,  Tatiana G Kutateladze 11
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
  • 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Chiba, 277-0882, Japan.
  • 3 Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division, Quebec City, QC, G1R 3S3, Canada.
  • 4 Department of Physics, Ohio State University, Columbus, OH, 43210, USA.
  • 5 Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 6 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • 7 Department of Biochemistry, University of Colorado, Boulder, CO, 80303, USA.
  • 8 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
  • 9 Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division, Quebec City, QC, G1R 3S3, Canada. [email protected].
  • 10 Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata, 997-0052, Japan. [email protected].
  • 11 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA. [email protected].
  • # Contributed equally.
PMID: 36754959 DOI: 10.1038/s41467-023-36368-5
Abstract

Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.

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