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Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX

Author

Listed:
  • Dominik Hoelper

    (School of Medicine and Public Health, University of Wisconsin
    University of Wisconsin)

  • Hongda Huang

    (Memorial Sloan-Kettering Cancer Center
    South University of Science and Technology)

  • Aayushi Y. Jain

    (School of Medicine and Public Health, University of Wisconsin
    University of Wisconsin)

  • Dinshaw J. Patel

    (Memorial Sloan-Kettering Cancer Center)

  • Peter W. Lewis

    (School of Medicine and Public Health, University of Wisconsin
    University of Wisconsin)

Abstract

The ATRX–DAXX histone chaperone complex incorporates the histone variant H3.3 at heterochromatic regions in a replication-independent manner. Here, we present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX. We use single amino acid substitutions in DAXX that abrogate formation of the complex to explore ATRX-dependent and ATRX-independent functions of DAXX. We find that the repression of specific murine endogenous retroviruses is dependent on DAXX, but not on ATRX. In support, we reveal the existence of two biochemically distinct DAXX-containing complexes: the ATRX–DAXX complex involved in gene repression and telomere chromatin structure, and a DAXX–SETDB1–KAP1–HDAC1 complex that represses endogenous retroviruses independently of ATRX and H3.3 incorporation into chromatin. We find that histone H3.3 stabilizes DAXX protein levels and can affect DAXX-regulated gene expression without incorporation into nucleosomes. Our study demonstrates a nucleosome-independent function for the H3.3 histone variant.

Suggested Citation

  • Dominik Hoelper & Hongda Huang & Aayushi Y. Jain & Dinshaw J. Patel & Peter W. Lewis, 2017. "Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01206-y
    DOI: 10.1038/s41467-017-01206-y
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    Cited by:

    1. Sophia Groh & Anna Viktoria Milton & Lisa Katherina Marinelli & Cara V. Sickinger & Angela Russo & Heike Bollig & Gustavo Pereira de Almeida & Andreas Schmidt & Ignasi Forné & Axel Imhof & Gunnar Scho, 2021. "Morc3 silences endogenous retroviruses by enabling Daxx-mediated histone H3.3 incorporation," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Iqbal Mahmud & Guimei Tian & Jia Wang & Tarun E. Hutchinson & Brandon J. Kim & Nikee Awasthee & Seth Hale & Chengcheng Meng & Allison Moore & Liming Zhao & Jessica E. Lewis & Aaron Waddell & Shangtao , 2023. "DAXX drives de novo lipogenesis and contributes to tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Kentaro Mochizuki & Jafar Sharif & Kenjiro Shirane & Kousuke Uranishi & Aaron B. Bogutz & Sanne M. Janssen & Ayumu Suzuki & Akihiko Okuda & Haruhiko Koseki & Matthew C. Lorincz, 2021. "Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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