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MORC2 is a phosphorylation-dependent DNA compaction machine

Author

Listed:
  • Winnie Tan

    (1G Royal Parade
    The University of Melbourne
    University of Melbourne)

  • Jeongveen Park

    (Seoul National University)

  • Hariprasad Venugopal

    (Monash University)

  • Jieqiong Lou

    (The University of Melbourne)

  • Prabavi Shayana Dias

    (1G Royal Parade
    The University of Texas at Dallas)

  • Pedro L. Baldoni

    (1G Royal Parade
    The University of Melbourne)

  • Kyoung-Wook Moon

    (Seoul National University)

  • Toby A. Dite

    (1G Royal Parade
    The University of Melbourne)

  • Christine R. Keenan

    (1G Royal Parade
    The University of Melbourne
    The University of Melbourne)

  • Alexandra D. Gurzau

    (1G Royal Parade
    The University of Melbourne)

  • Joonyoung Lee

    (Seoul National University)

  • Timothy M. Johanson

    (1G Royal Parade
    The University of Melbourne)

  • Andrew Leis

    (1G Royal Parade
    The University of Melbourne)

  • Jumana Yousef

    (1G Royal Parade
    The University of Melbourne)

  • Vineet Vaibhav

    (1G Royal Parade
    The University of Melbourne)

  • Laura F. Dagley

    (1G Royal Parade
    The University of Melbourne)

  • Ching-Seng Ang

    (The University of Melbourne)

  • Laura D. Corso

    (1G Royal Parade
    The University of Melbourne)

  • Chen Davidovich

    (Monash University)

  • Stephin J. Vervoort

    (1G Royal Parade
    The University of Melbourne)

  • Gordon K. Smyth

    (1G Royal Parade
    The University of Melbourne)

  • Marnie E. Blewitt

    (1G Royal Parade
    The University of Melbourne)

  • Rhys S. Allan

    (1G Royal Parade
    The University of Melbourne)

  • Elizabeth Hinde

    (The University of Melbourne)

  • Sheena D’Arcy

    (The University of Texas at Dallas)

  • Je-Kyung Ryu

    (Seoul National University)

  • Shabih Shakeel

    (1G Royal Parade
    The University of Melbourne
    University of Melbourne
    The University of Melbourne)

Abstract

The Microrchidia (MORC) family of chromatin-remodelling ATPases is pivotal in forming higher-order chromatin structures that suppress transcription. The exact mechanisms of MORC-induced chromatin remodelling have been elusive. Here, we report an in vitro reconstitution of full-length MORC2, the most commonly mutated MORC member, linked to various cancers and neurological disorders. MORC2 possesses multiple DNA-binding sites that undergo structural rearrangement upon DNA binding. MORC2 locks onto the DNA using its C-terminal domain (CTD) and acts as a clamp. A conserved phosphate-interacting motif within the CTD was found to regulate ATP hydrolysis and cooperative DNA binding. Importantly, MORC2 mediates chromatin remodelling via ATP hydrolysis-dependent DNA compaction in vitro, regulated by the phosphorylation state of its CTD. These findings position MORC2 CTD phosphorylation as a critical regulator of chromatin remodelling and a promising therapeutic target.

Suggested Citation

  • Winnie Tan & Jeongveen Park & Hariprasad Venugopal & Jieqiong Lou & Prabavi Shayana Dias & Pedro L. Baldoni & Kyoung-Wook Moon & Toby A. Dite & Christine R. Keenan & Alexandra D. Gurzau & Joonyoung Le, 2025. "MORC2 is a phosphorylation-dependent DNA compaction machine," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60751-z
    DOI: 10.1038/s41467-025-60751-z
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    References listed on IDEAS

    as
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