Fig. 7. Disruption of RRM-1 increases TDP-43 binding to the chromatin and/or nuclear matrix. Under normal conditions, TDP-43 is found in the soluble nuclear fraction (S1) and bound to the nuclear matrix portion. Deletion of RRM-1 or mutation of key RNA and/or DNA-binding residues, shifts the equilibrium towards the bound fraction. RNA and/or DNA-binding mediated through RRM-1 may require protein mobility in the soluble fraction of the nucleus, whereas RRM-2 mediates recruitment to chromatin and/or the nuclear matrix.