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ASXLs binding to the PHD2/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers

Author

Listed:
  • Yi Zhang

    (University of Colorado School of Medicine
    Case Western Reserve University)

  • Guojia Xie

    (National Institute of Diabetes and Digestive and Kidney Diseases, NIH)

  • Ji-Eun Lee

    (National Institute of Diabetes and Digestive and Kidney Diseases, NIH)

  • Mohamad Zandian

    (University of Colorado School of Medicine)

  • Deepthi Sudarshan

    (Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center)

  • Benjamin Estavoyer

    (Maisonneuve-Rosemont Hospital Research Center)

  • Caroline Benz

    (Uppsala University)

  • Tiina Viita

    (Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center)

  • Golareh Asgaritarghi

    (Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center)

  • Catherine Lachance

    (Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center)

  • Clémence Messmer

    (Maisonneuve-Rosemont Hospital Research Center)

  • Leandro Simonetti

    (Uppsala University)

  • Vikrant Kumar Sinha

    (University of Colorado School of Medicine)

  • Jean-Philippe Lambert

    (Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center)

  • Yu-Wen Chen

    (Academia Sinica)

  • Shu-Ping Wang

    (Academia Sinica)

  • Ylva Ivarsson

    (Uppsala University)

  • El Bachir Affar

    (Maisonneuve-Rosemont Hospital Research Center
    University of Montréal)

  • Jacques Côté

    (Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center)

  • Kai Ge

    (National Institute of Diabetes and Digestive and Kidney Diseases, NIH)

  • Tatiana G. Kutateladze

    (University of Colorado School of Medicine)

Abstract

The human methyltransferase and transcriptional coactivator MLL4 and its paralog MLL3 are frequently mutated in cancer. MLL4 and MLL3 monomethylate histone H3K4 and contain a set of uncharacterized PHD fingers. Here, we report a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL4 and MLL3 that bind to ASXL2, a component of the Polycomb repressive H2AK119 deubiquitinase (PR-DUB) complex. The structure of MLL4 PHD2/3 in complex with the MLL-binding helix (MBH) of ASXL2 and mutational analyses reveal the molecular mechanism which is conserved in homologous ASXL1 and ASXL3. The native interaction of the Trithorax MLL3/4 complexes with the PR-DUB complex in vivo depends solely on MBH of ASXL1/2, coupling the two histone modifying activities. ChIP-seq analysis in embryonic stem cells demonstrates that MBH of ASXL1/2 is required for the deubiquitinase BAP1 recruitment to MLL4-bound active enhancers. Our findings suggest an ASXL1/2-dependent functional link between the MLL3/4 and PR-DUB complexes.

Suggested Citation

  • Yi Zhang & Guojia Xie & Ji-Eun Lee & Mohamad Zandian & Deepthi Sudarshan & Benjamin Estavoyer & Caroline Benz & Tiina Viita & Golareh Asgaritarghi & Catherine Lachance & Clémence Messmer & Leandro Sim, 2024. "ASXLs binding to the PHD2/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49391-x
    DOI: 10.1038/s41467-024-49391-x
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