MORC2 phosphorylation fine tunes its DNA compaction activity

ABSTRACT: Variants in the poorly characterized oncoprotein, MORC2, a chromatin remodeling ATPase, lead to defects in epigenetic regulation and DNA damage response. MORC2 variants are associated with multiple cancers and neurological disorders. The C-terminal domain (CTD) of MORC2is often phosphorylated in DNA damage response and is known to induce cancer progression in in vivo and in vitro cancer models. However, it remains unclear how MORC2 CTD and its phosphorylation impacts its chromatin remodeling activity. Here, we report a molecular characterization of full-length, phosphorylated MORC2.We show thatMORC2 preferentially binds open chromatin, has multiple DNA binding sites with varying affinities and acts as a DNA sliding clamp. We identified a phosphate interacting motif within the CTD that dictates ATP hydrolysis and cooperative DNA binding. The DNA binding impacts several structural domains within the N-terminal ATPase region. We provide the first visual proof that MORC2 induces chromatin remodeling through ATP hydrolysis-dependent DNA compaction, where the speed of compaction is affected by its phosphorylation state. Together, our results reveal that phosphorylation of MORC2 CTD modulates its chromatin remodeling and could be an attractive target for therapeutics.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Charcot-marie-tooth Disease,Spinal Muscular Atrophy,Breast Cancer

SUBMITTER: Sheena D'Arcy  

LAB HEAD: Sheena D'Arcy

PROVIDER: PXD053379 | Pride | 2025-07-14

REPOSITORIES: Pride