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

Dustin C. Becht, Brianna J. Klein, Akinori Kanai, Suk Min Jang, Khan L. Cox, Bing-Rui Zhou, Sabrina K. Phanor, Yi Zhang, Ruo-Wen Chen, Christopher C. Ebmeier, Catherine Lachance, Maxime Galloy, Amelie Fradet-Turcotte, Martha L. Bulyk, Yawen Bai, Michael G. Poirier, Jacques Côté (), Akihiko Yokoyama () and Tatiana G. Kutateladze ()
Additional contact information
Dustin C. Becht: University of Colorado School of Medicine
Brianna J. Klein: University of Colorado School of Medicine
Akinori Kanai: the University of Tokyo
Suk Min Jang: Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division
Khan L. Cox: Ohio State University
Bing-Rui Zhou: National Institutes of Health
Sabrina K. Phanor: Brigham and Women’s Hospital and Harvard Medical School
Yi Zhang: University of Colorado School of Medicine
Ruo-Wen Chen: Ohio State University
Christopher C. Ebmeier: University of Colorado
Catherine Lachance: Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division
Maxime Galloy: Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division
Amelie Fradet-Turcotte: Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division
Martha L. Bulyk: Brigham and Women’s Hospital and Harvard Medical School
Yawen Bai: National Institutes of Health
Michael G. Poirier: Ohio State University
Jacques Côté: Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division
Akihiko Yokoyama: National Cancer Center
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36368-5

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