Gain-of-function RNA Polymerase II partitioning is a shared feature of diverse oncogenic fusions

Condensates regulate transcription by selectively compartmentalizing biomolecules, yet the rules of selectivity and their relationship to function remain enigmatic. To identify rules with links to function, we leverage the genetic/evolutionary selection bias of condensate-promoting oncofusions. Focusing on the three most frequent oncofusions driving translocation renal cell carcinoma, we find that they promote the formation of condensates that activate transcription by gain-of-function RNA Polymerase II partitioning through a shared signature of elevated p and p-interacting residues and depletion of aliphatic residues. This signature is shared among a broad set of oncofusions associated with diverse cancers. We find that this signature is necessary and sufficient for RNA Polymerase II partitioning, gene activation, and cancer cell phenotypes. Our results reveal that dysregulated condensate selectivity is a shared molecular mechanism of diverse oncofusions, highlighting the functional role of condensate composition and the power of genetics in investigating relationships between condensate selectivity rules and function.