Deciphering the molecular mechanisms of FET fusion oncoprotein–DNA hollow co-condensates

Abstract

Abstract Biomolecules such as nucleic acids and proteins can undergo phase separation to form biomolecular condensates with diverse architectures. Here, we report that the FUS/EWS/TAF15 family fusion oncoprotein FUS-ERG forms hollow co-condensates with double-stranded DNA containing GGAA microsatellites. Through a combination of biochemical assays, super-resolution imaging, and mathematical modeling, we reveal that the interior surface of hollow co-condensates exhibits properties distinct from those of the external surface, a phenomenon we term nested asymmetric phase separation. Furthermore, we harness FUS-ERG for DNA-based information manipulation and demonstrated the hollow condensate morphology uniquely enhances data sorting specificity, enabling targeted DNA deletion within dsDNA libraries and facilitating dynamic, hierarchical data selection. These findings provide critical insights into the biophysical mechanisms underlying multicomponent phase-separated cellular bodies and establish a foundation for leveraging condensate morphology in biotechnology.