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Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1. | LitMetric
Ewing sarcoma breakpoint region 1 () encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of , its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5' isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5' polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5' isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the gene leading to either early transcription termination, or breakpoint formation.
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