MORC2 is a phosphorylation-dependent DNA compaction machine

Tan, W; Park, J; Venugopal, H; Lou, J; Dias, PS; Baldoni, PL; Moon, KW; Dite, TA; Keenan, CR; Gurzau, AD; Lee, J; Johanson, TM; Leis, A; Yousef, J; Vaibhav, V; Dagley, LF; Ang, CS; Corso, LD; Davidovich, C; Vervoort, SJ; Smyth, GK; Blewitt, ME; Allan, RS; Hinde, E; D&#39;Arcy, S; Ryu, JK; Shakeel, S

Author(s): Tan, W; Park, J; Venugopal, H; Lou, J; Dias, PS; Baldoni, PL; Moon, KW; Dite, TA; Keenan, CR; Gurzau, AD; Lee, J; Johanson, TM; Leis, A; Yousef, J; Vaibhav, V; Dagley, LF; Ang, CS; Corso, LD; Davidovich, C; Vervoort, SJ; Smyth, GK; Blewitt, ME; Allan, RS; Hinde, E; D'Arcy, S; Ryu, JK; Shakeel, S;
Details: Publication Year 2025-07-01,Volume 16,Issue #1,Page 5606
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: Phosphorylation; *DNA/metabolism/chemistry; Humans; *Chromatin Assembly and Disassembly; Adenosine Triphosphate/metabolism; *Transcription Factors/metabolism/genetics/chemistry; Protein Domains; Binding Sites; Protein Binding; Hydrolysis; Chromatin/metabolism
Research Division(s): Structural Biology; Advanced Technology and Biology; Immunology; Genetics and Gene Regulation; Bioinformatics and Computational Biology
PubMed ID: 40593625
Publisher's Version: https://doi.org/10.1038/s41467-025-60751-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-60751-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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