The Role of Phase-Separated Condensates in Fusion Oncoprotein–Driven Cancers
Hazheen K. Shirnekhi, Bappaditya Chandra, Richard W. Kriwacki
Abstract
Fusion oncoproteins (FOs) resulting from in-frame chromosomal translocations are associated with many aggressive cancers with poor patient outcomes. Several FOs are now understood to perform their oncogenic functions within biomolecular condensates formed through liquid-liquid phase separation (LLPS). Two classes of phase separating FOs have emerged, those that form nuclear condensates and alter chromatin biology, including gene expression, and others that form cytoplasmic condensates and promote aberrant signaling, including RAS/MAPK signaling. The amino acid sequences of these FO classes display LLPS-prone intrinsically disordered regions (IDRs) and folded domains within their amino acid sequences that synergistically interact with themselves and other biomolecules to promote condensate formation. This review summarizes the roles of LLPS in the oncogenic functions of these two FO classes, and also discusses examples of FOs that inhibit physiological LLPS in normal cells. Finally, the article discusses the sequence features commonly associated with LLPS and their enrichment in many FOs.