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; Shabih Shakeel

doi:10.1038/s41467-025-60751-z

MORC2 is a phosphorylation-dependent DNA compaction machine

Nat Commun. 2025 Jul 1;16(1):5606. doi: 10.1038/s41467-025-60751-z.

Authors

Winnie Tan^{1

2

3}, Jeongveen Park⁴, Hariprasad Venugopal^#⁵, Jieqiong Lou^#⁶, Prabavi Shayana Dias^#^{1

7}, Pedro L Baldoni^#^{1

2}, Kyoung-Wook Moon^#⁴, Toby A Dite^#^{1

2}, Christine R Keenan^{1

2

6}, Alexandra D Gurzau^{1

2}, Joonyoung Lee⁴, Timothy M Johanson^{1

2}, Andrew Leis^{1

2}, Jumana Yousef^{1

2}, Vineet Vaibhav^{1

2}, Laura F Dagley^{1

2}, Ching-Seng Ang⁸, Laura D Corso^{1

2}, Chen Davidovich⁵, Stephin J Vervoort^{1

2}, Gordon K Smyth^{1

9}, Marnie E Blewitt^{1

2}, Rhys S Allan^{1

2}, Elizabeth Hinde⁶, Sheena D'Arcy⁷, Je-Kyung Ryu¹⁰, Shabih Shakeel^{11

12

13

14}

Affiliations

¹ WEHI, 1G Royal Parade, Parkville, VIC, 3052, Australia.
² Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3052, Australia.
³ ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
⁴ Department of Physics and Astronomy, Seoul National University, Seoul, Republic of Korea.
⁵ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3168, Australia.
⁶ Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, 3052, Australia.
⁷ Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX, 75080, USA.
⁸ The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3052, Australia.
⁹ School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁰ Department of Physics and Astronomy, Seoul National University, Seoul, Republic of Korea. prof.love@snu.ac.kr.
¹¹ WEHI, 1G Royal Parade, Parkville, VIC, 3052, Australia. shakeel.s@wehi.edu.au.
¹² Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3052, Australia. shakeel.s@wehi.edu.au.
¹³ ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia. shakeel.s@wehi.edu.au.
¹⁴ Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, 3052, Australia. shakeel.s@wehi.edu.au.

^# Contributed equally.

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.

MeSH terms

Adenosine Triphosphate / metabolism
Binding Sites
Chromatin / metabolism
Chromatin Assembly and Disassembly*
DNA* / chemistry
DNA* / metabolism
Humans
Hydrolysis
Phosphorylation
Protein Binding
Protein Domains
Transcription Factors* / chemistry
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

DNA
Adenosine Triphosphate
Transcription Factors
Chromatin

Grants and funding

GNT 2016827/Department of Health | National Health and Medical Research Council (NHMRC)