Role of Phase separation by fusion oncoproteins in oncogenesis

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SUMMARY Gene translocations that fuse segments of two different genes (termed parents) are known to drive oncogenesis in myriad cancers. Expression of in-frame translocations yields fusion oncoproteins (FOs) with hybrid functional properties that aberrantly control critical biological processes and, ultimately, cause unchecked cell proliferation and oncogenesis. FOs are often abnormal transcription factors that fuse unstructured segments of one parent that function as activation domains to a DNA or chromatin binding domain of the other. These FOs result in abnormal gene expression that transforms cells and drives oncogenesis. Our preliminary computational results show that FOs often contain intrinsically disordered regions (IDRs) that display sequence features associated with the ability to undergo liquid-liquid phase separation (LLPS), a process now appreciated to mediate the formation and function of numerous cellular bodies, including membrane-less organelles and, importantly, nuclear transcription centers with punctate morphology. Our computational analyses of thousands of clinically documented fusion oncogenes show that a significant portion of the associated FOs contain LLPS-prone IDRs. Based on this observation, we hypothesize that a set of FOs transform cells by forming aberrant transcription centers through phase separation; other FOs containing LLPS-prone IDRs may form aberrant cellular puncta that host different functions. Further, we hypothesize that FOs represent a rich source of proteins which, through analysis in cells and in vitro, and through computational analyses, will reveal novel sequence and conformational features associated with phase separation. These hypotheses will be tested through three specific aims.