Mechanisms of Important Fusions

Question 1

TMPRSS2::ERG mechanism

Answer 1

TMPRSS2 is a transmembrane protease expressed in prostate under an androgen-responsive promoter.

ERG is an ETS family transcription factor (containing an ETS-family DNA binding domain). Other family members include FLI1, ETS1, ETS2, ETV1, ETV6, ELK3. These factors must dimerize, either with themselves, other ETS-family transcription factors, the androgen receptor, or AP-1 complex members (FOS, JUN, etc) in order to bind DNA and initiate transcription.

The TMPRSS2::ERG fusion places ERG under the control of this promoter, making ERG expression upregulated directly by androgens signaling.

Translocations usually involve one of the fragile breakpoints in intron 1 or intron 2 of TMPRSS2, creating a fusion between exon 1 or 2 of TMPRSS2 and exon 4 of ERG.

Question 2

EWSR1::FLI1 mechanism

Answer 2

EWSR1’s N-terminal region contains a disordered Prion-like domain (which may produce liquid-liquid phase separation), while FLI1’s C-terminal region contains its DNA-binding domain and enables transcription of downstream FLI1 targets (ETS-motif).

The EWSR1::FLI1 protein also possesses the unique ability to turn silent GGAA repeat microsatellite sequences into enhancers (NOT an ability of normal ETS transcription factors).