# Role of Phase separation by fusion oncoproteins in oncogenesis

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $627,217

## Abstract

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.

## Key facts

- **NIH application ID:** 10305649
- **Project number:** 5R01CA246125-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Ashok A Deniz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $627,217
- **Award type:** 5
- **Project period:** 2019-12-06 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305649

## Citation

> US National Institutes of Health, RePORTER application 10305649, Role of Phase separation by fusion oncoproteins in oncogenesis (5R01CA246125-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10305649. Licensed CC0.

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