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MORC2 phosphorylation fine tunes its DNA compaction activity

ABSTRACT: Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. MORC2 variants are associated with multiple cancers and neurological disorders1,2. The C-terminal domain (CTD) of MORC2 is often phosphorylated in DNA damage response and is known to induce cancer progression in in vivo and in vitro cancer models3-5. However, it remains unclear how MORC2 CTD and its phosphorylation impacts its chromatin remodelling activity. Here, we report a molecular characterisation of full-length, phosphorylated MORC2. We show that MORC2 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 remodelling 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 remodelling and could be an attractive target for therapeutics.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin

SUBMITTER: Laura Dagley

LAB HEAD: Shabih Shakeel

PROVIDER: PXD053383 | Pride | 2025-05-05

REPOSITORIES: Pride

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Project description:SWI/SNF-family chromatin remodelling complexes conduct nucleosome sliding and ejection to provide DNA-binding proteins access to their sites in chromatin. RSC is an essential and abundant SWI/SNF-family chromatin remodeller from S. cerevisiae that both slides and ejects nucleosomes. However, how ejection versus sliding is chosen, regulated and implemented by any remodeller remains largely unknown. The RSC catalytic subunit Sth1 conducts ATP-dependent DNA translocation, pumping DNA around the nucleosome, providing a property that might underlie both sliding and ejection. Sth1 shares with other SWI/SNF-family ATPases direct binding to two nuclear actin-related proteins (ARPs), but how ARPs impact DNA translocation, sliding and ejection is unknown. Here, we reveal that nucleosome ejection by RSC requires ARPs, and that ARPs improve ‘coupling’ – the efficiency of DNA translocation by Sth1 relative to ATP hydrolysis – thus, enhancing DNA translocation. We further characterize two domains within Sth1 (termed PTH and P1), showing they separately regulate ATP hydrolysis or ‘coupling’, respectively. Interestingly, gain-of-function PTH or P1 mutations suppress arpΔ lethality, and improve ATPase or coupling activities, enabling Sth1 to efficiently slide and eject nucleosomes without ARPs. Moreover, PTH mutations greatly improved DNA translocation velocity. Overall, our results provide a logic for regulating nucleosome sliding versus ejection: both modes involve DNA translocation, but ejection requires a higher magnitude. Here, low-to-moderate ATPase and coupling activity integrate to confer low-to-moderate sliding, whereas high ATPase and/or coupling combine to provide efficient and rapid DNA translocation, consistent with the simultaneous rupture of multiple histone-DNA contacts, causing histone loss/ejection. Our discovery of an ARP module and regulatory domains that regulate sliding and ejection suggests a mechanistic platform through which activators and histone epitopes may guide the remodelling outcome of SWI/SNF-family chromatin remodellers.

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MORC2 phosphorylation fine tunes its DNA compaction activity

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