RT Journal Article
SR Electronic
T1 FUS Oncofusion Protein Condensates Recruit mSWI/SNF Chromatin Remodelers via Heterotypic Interactions Between Prion-like Domains
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.23.440992
DO 10.1101/2021.04.23.440992
A1 Richoo B. Davis
A1 Taranpreet Kaur
A1 Mahdi Muhammad Moosa
A1 Priya R. Banerjee
YR 2021
UL http://biorxiv.org/content/early/2021/04/23/2021.04.23.440992.abstract
AB Fusion transcription factors generated by genomic translocations are common drivers of several types of cancers including sarcomas and leukemias. Oncofusions of the FET (FUS, EWSR1, and TAF15) family of proteins result from fusion of the prion-like domain (PLD) of FET proteins to the DNA-binding domain (DBD) of certain transcription regulators and are implicated in aberrant transcriptional programs through interactions with chromatin remodelers. Here, we show that FUS-DDIT3, a FET oncofusion protein, undergoes PLD-mediated phase separation into liquid-like condensates. Nuclear FUS-DDIT3 condensates can recruit essential components of the global transcriptional machinery such as the chromatin remodeler SWI/SNF. The recruitment of mammalian SWI/SNF is driven by heterotypic PLD-PLD interactions between FUS-DDIT3 and core subunits of SWI/SNF, such as the catalytic component BRG1. Further experiments with single-molecule correlative force-fluorescence microscopy support a model wherein the fusion protein forms condensates on DNA surface and enrich BRG1 to activate transcription by ectopic chromatin remodeling. Similar PLD-driven co-condensation of mSWI/SNF with transcription factors can be employed by other oncogenic fusion proteins with a generic PLD-DBD domain architecture for global transcriptional reprogramming.Competing Interest StatementThe authors have declared no competing interest.