GSE122308
Material properties of biomolecular condensates regulates RNA splicing and tumorigenesis
It remains largely unclear how material properties of biomolecular condensates impact physiological and pathological processes such as cancer. Here we show that AKAP95, a nuclear protein involved in gene regulation, plays an important role in tumorigenesis through directly regulating mRNA splicing. We show that AKAP95, through an intrinsic disordered region (IDR), forms liquid-like droplets in vitro and dynamic foci in nucleus. We have also identified key residues in IDR whose mutations to different residues perturb AKAP95 condensation in opposite directions. Importantly, the biological activity of AKAP95 in splice regulation is affected by either disruption of liquid condensation or enhancing the gelation of the assembly. We then show that the ability of AKAP95 in overcoming oncogene-induced senescence requires AKAP95 in an appropriate window of liquidity. These results thus link phase separation to tumorigenesis and uncover an important role of regulating the material property of protein condensates in disease including cancer. Overall design: Gene expression and splicing of MDA-MB-MDA-MB-231 (control, AKAP95-knockdown, -rescued) cells; oncogene Myc-induced MEF (Akap95 heterozygous and knockout) rescued with or without human AKAP95 variants with different phase separation properties were determined by RNA-seq.