PT  - JOURNAL ARTICLE
AU  - Farahi, Nazanin
AU  - Lazar, Tamas
AU  - Tompa, Peter
AU  - Mészáros, Bálint
AU  - Pancsa, Rita
TI  - Phase-separating fusion proteins drive cancer by dysregulating transcription through ectopic condensates
AID  - 10.1101/2023.09.20.558425
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.09.20.558425
4099  - http://biorxiv.org/content/early/2023/11/20/2023.09.20.558425.short
4100  - http://biorxiv.org/content/early/2023/11/20/2023.09.20.558425.full
AB  - Numerous cellular processes rely on biomolecular condensates formed through liquid-liquid phase separation (LLPS), thus, perturbations of LLPS underlie various diseases. We found that proteins initiating LLPS are frequently implicated in somatic cancers, even surpassing their involvement in neurodegeneration. Cancer-associated LLPS scaffolds are connected to all cancer hallmarks and tend to be oncogenes with dominant genetic effects lacking therapeutic options. Since most of them act as oncogenic fusion proteins (OFPs), we undertook a systematic analysis of cancer driver OFPs by assessing their module-level molecular functions. We identified both known and novel combinations of molecular functions that are specific to OFPs and thus have a high potential for driving tumorigenesis. Protein regions driving condensate formation show an increased association with DNA- or chromatin-binding domains of transcription regulators within OFPs, indicating a common molecular mechanism underlying several soft tissue sarcomas and hematologic malignancies where phase-separation-prone OFPs form abnormal, ectopic condensates along the DNA, and thereby dysregulate gene expression programs.Competing Interest StatementThe authors have declared no competing interest.