Abstract: Nuclear speckles (NSs) are viscoelastic network fluids formed via phase separation coupled to percolation (PSCP). Intermolecular crosslinks of SRRM2 lead to the emergence of system-spanning networks, although the physicochemical grammar governing SRRM2 PSCP remains poorly decoded. Here, we demonstrate that SRRM2 is extensively phosphorylated within the intrinsically disordered region (IDR), creating alternating charge blocks. We show that this specific charge pattern does not markedly alter the condensation threshold of SRRM2 in cells. Instead, SRRM2 charge blocks intensify intra-network molecular interactions to modulate the material properties of mesoscopic SRRM2 condensates. We further identify casein kinase 2 (CK2) as the upstream enzyme to catalyze SRRM2 phosphorylation. Phosphorylation of SRRM2 IDR by CK2 facilitates NS relaxation, which is associated with enhanced efficiency of mRNA splicing to safeguard genome stability during DNA damage. Our findings reveal important regulatory mechanisms of charge blocks in modulating the material properties and functions of biomolecular condensates in human cells.

Link: https://doi.org/10.1016/j.molcel.2025.03.016