Nature: EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma
Aparna Gorthi, July Carolina Romero, Eva Loranc, Lin Cao, Liesl A. Lawrence, Elicia Goodale, Amanda Balboni Iniguez, Xavier Bernard, V. Pragathi Masamsetti, Sydney Roston, Elizabeth R. Lawlor, Jeffrey A. Toretsky, Kimberly Stegmaier, Stephen L. Lessnick, Yidong Chen & Alexander J. R. Bishop
Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein1. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in the regulation of damage-induced transcription, accumulation of R-loops, and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 and the elongating transcription machinery. Finally, we uncover a role for EWSR1 in the transcriptional response to damage, suppressing R-loops, and promoting homologous recombination. Our findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors), and highlight a class of BRCA-deficient-like tumors.