Structural Maintenance of Chromosomes Hinge Domain-containing protein 1 (SMCHD1) has been established as an epigenetic regulator, with critical roles in X-chromosome inactivation, autosomal gene silencing and genomic imprinting. Variations in SMCHD1 have also been associated with two human conditions: facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS). There has therefore been a growing interest in unveiling SMCHD1’s atomic structure and the molecular mechanisms underlying its function in both a healthy and diseased state.
While we have previously shown that SMCHD1 is able to interact with nucleic acids via its C-terminal hinge domain, we have now identified a novel DNA-binding region that is located downstream of SMCHD1’s N-terminal ATPase module. Using site-directed mutagenesis and structural analysis via cryo-EM, we provide a new insight into SMCHD1’s DNA-binding mode. Furthermore, we uncovered that the presence of either single- or double-stranded DNA is able to stimulate SMCHD1’s ATPase activity in vitro. This finding raises further questions about how exactly DNA is able to stimulate SMCHD1’s catalytic function, and why this mechanism may be required.