A protein-DNA surface hydrogel mechanically protects the cell nucleus

Abstract

The nuclear envelope protects the genome from mechanical stress during processes such as migration, division, and compression1-6, but how it buffers forces at the scale of DNA remains unclear. Here, we utilize optical tweezers to show that a multivalent protein-DNA co-condensate containing the nuclear envelope protein LEM27,8 and the DNA-binding protein BAF 9,10 shield DNA beyond its melting point at 65 pN11. Under load, their collective assembly induces an unconventional DNA stiffening effect that provides mechanical reinforcement, dependent on the intrinsically disordered region (IDR) of LEM2. At the nuclear surface, these components form an elastic surface hydrogel in which LEM2 IDR-IDR interactions contract the surface hydrogel relative to its relaxed state, introducing a pre-stress in the lamin network. Inside cells, this surface hydrogel model can recapitulate elastic properties of the nuclear envelope measured via AFM indentation experiments as well as nuclear morphology, using parameters obtained at the molecular scale by use of optical tweezers. Disruption of the surface hydrogel increases DNA damage and micronuclei formation during nuclear deformation. These findings reveal a load-bearing, mesoscale surface hydrogel that reinforces the nucleus and expands the functional repertoire of biomolecular condensates to include DNA protection under mechanical stress.