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
2025-07-01
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.