MORC2 is a phosphorylation-dependent DNA compaction machine
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.
Article Details
Authors (27)
Winnie Tan
Jeongveen Park
Hariprasad Venugopal
Ramaciotti Centre for Cryo Electron Microscopy, Monash University
Jieqiong Lou
Prabavi Shayana Dias
Pedro L. Baldoni
Kyoung-Wook Moon
Toby A. Dite
Walter and Eliza Hall Institute of Medical Research
Christine R. Keenan
Alexandra D. Gurzau
Joonyoung Lee
Timothy M. Johanson
Andrew Leis
Jumana Yousef
Walter and Eliza Hall Institute of Medical Research
Vineet Vaibhav
Laura F. Dagley
Walter and Eliza Hall Institute of Medical Research
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
Department of Chemistry and Biochemistry, The University of Texas at Dallas
Je-Kyung Ryu
Shabih Shakeel