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

Author

Listed:
  • 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
    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)

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.

Suggested Citation

  • 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 Gal, 2023. "MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36368-5
    DOI: 10.1038/s41467-023-36368-5
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    References listed on IDEAS

    as
    1. Jonathan B. Baell & David J. Leaver & Stefan J. Hermans & Gemma L. Kelly & Margs S. Brennan & Natalie L. Downer & Nghi Nguyen & Johannes Wichmann & Helen M. McRae & Yuqing Yang & Ben Cleary & H. Rache, 2018. "Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth," Nature, Nature, vol. 560(7717), pages 253-257, August.
    2. Catherine A. Musselman & Matthew D. Gibson & Erik W. Hartwick & Justin A. North & Jovylyn Gatchalian & Michael G. Poirier & Tatiana G. Kutateladze, 2013. "Binding of PHF1 Tudor to H3K36me3 enhances nucleosome accessibility," Nature Communications, Nature, vol. 4(1), pages 1-9, December.
    3. Yi Zhang & Kyle Brown & Yucong Yu & Ziad Ibrahim & Mohamad Zandian & Hongwen Xuan & Steven Ingersoll & Thomas Lee & Christopher C. Ebmeier & Jiuyang Liu & Daniel Panne & Xiaobing Shi & Xiaojun Ren & T, 2021. "Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Brianna J. Klein & Suk Min Jang & Catherine Lachance & Wenyi Mi & Jie Lyu & Shun Sakuraba & Krzysztof Krajewski & Wesley W. Wang & Simone Sidoli & Jiuyang Liu & Yi Zhang & Xiaolu Wang & Becka M. Warfi, 2019. "Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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