MORC2 is a phosphorylation-dependent DNA compaction machine

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 Lee, Timothy M. Johanson, Andrew Leis, Jumana Yousef, Vineet Vaibhav, Laura F. Dagley, Ching-Seng Ang, Laura D. Corso, Chen Davidovich, Stephin J. Vervoort, Gordon K. Smyth, Marnie E. Blewitt, Rhys S. Allan, Elizabeth Hinde, Sheena D’Arcy, Je-Kyung Ryu () and Shabih Shakeel ()
Additional contact information
Winnie Tan: 1G Royal Parade
Jeongveen Park: Seoul National University
Hariprasad Venugopal: Monash University
Jieqiong Lou: The University of Melbourne
Prabavi Shayana Dias: 1G Royal Parade
Pedro L. Baldoni: 1G Royal Parade
Kyoung-Wook Moon: Seoul National University
Toby A. Dite: 1G Royal Parade
Christine R. Keenan: 1G Royal Parade
Alexandra D. Gurzau: 1G Royal Parade
Joonyoung Lee: Seoul National University
Timothy M. Johanson: 1G Royal Parade
Andrew Leis: 1G Royal Parade
Jumana Yousef: 1G Royal Parade
Vineet Vaibhav: 1G Royal Parade
Laura F. Dagley: 1G Royal Parade
Ching-Seng Ang: The University of Melbourne
Laura D. Corso: 1G Royal Parade
Chen Davidovich: Monash University
Stephin J. Vervoort: 1G Royal Parade
Gordon K. Smyth: 1G Royal Parade
Marnie E. Blewitt: 1G Royal Parade
Rhys S. Allan: 1G Royal Parade
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

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60751-z

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