Biology subjects

Gurzau, A. D.

Publications and source records attributed to Gurzau, A. D..

3 recordsLinked to original sources

bioRxiv2026

DNA binding by ATPase-adjacent domains stimulates SMCHD1 ATPase activity

SMCHD1 is an epigenetic regulator in which heterozygous variants are reported in facioscapulohumeral muscular dystrophy (FSHD), as well as Bosma arhinia microphthalmia syndrome (BAMS). While we have previously shown that SMCHD1 is able to interact with nucleic acids via its hinge domain, we have now identified a second DNA-binding site that is located C-terminal to the ATPase domain and formed by two domains: the Bromo-adjacent homology (BAH) and immunoglobulin-like 1 (IGL-1) domains. Here, we report their mode of DNA-interaction and we present the first high-resolution structure of the wild-type human SMCHD1 ATPase using site-directed mutagenesis and structural analysis via cryo-EM. We also reveal that DNA-binding at the BAH-IGL-1 domains stimulates the ATPase activity of full-length SMCHD1 in vitro, and demonstrate in a mouse model that ATP hydrolysis is essential for SMCHD1 function in vivo. Together, these findings establish bidentate DNA binding and DNA-stimulated ATP hydrolysis as central features of SMCHD1 function, providing new mechanistic insight into how SMCHD1 regulates gene silencing. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/704097v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@12b2fd5org.highwire.dtl.DTLVardef@5152c7org.highwire.dtl.DTLVardef@111c487org.highwire.dtl.DTLVardef@17d8d0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

MORC2 phosphorylation fine tunes its DNA compaction activity

Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of MORC2, frequently phosphorylated in DNA damage, promotes cancer progression, but its role in chromatin remodelling remains unclear. Here, we report a molecular characterisation of full-length, phosphorylated MORC2, demonstrating its preference for binding open chromatin and functioning as a DNA sliding clamp. We identified a phosphate interacting motif within the CTD that dictates ATP hydrolysis rate and cooperative DNA binding. The DNA binding impacts several structural domains within the ATPase region. We provide the first visual proof that MORC2 induces chromatin remodelling through ATP hydrolysis-dependent DNA compaction, regulated by its phosphorylation state. These findings highlight phosphorylation of MORC2 CTD as a key modulator of chromatin remodelling, presenting it as a potential therapeutic target.

molecular biology↗

bioRxiv2021

SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets and at the facioscapulohumeral muscular dystrophy associated macro-array, D4Z4. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against another epigenetic regulator complex, PRC2, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1s role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease.

molecular biology↗