Ewing Sarcomas Phenocopy BRCA1-Deficient Tumors

Ewing sarcomas are sensitive to genotoxic agents including etoposide, but the molecular mechanisms underlying sensitivity have not been elucidated. These tumors are characterized by a chromosomal translocation that generates the EWS–FLI1 fusion protein, and Gorthi and colleagues uncovered a role for EWS–FLI1 in DNA damage–induced transcription that may explain the chemosensitivity observed in Ewing sarcoma. EWS–FLI1 expression conferred sensitivity to etoposide, and in Ewing sarcoma cells EWS–FLI1 increased basal levels of transcription, promoting transcriptional dysregulation in response to DNA damage. This dysregulated transcription resulted in an increased accumulation of R-loops (DNA–RNA hybrids), especially at highly expressed genes. R-loop accumulation induced replication stress but surprisingly did not induce homologous recombination. This effect could be induced by EWS–FLI1 expression or loss of EWSR1 function, suggesting that this effect may be due to a dominant negative function of EWS–FLI1 in repressing EWSR1. The impairment of homologous recombination in Ewing sarcoma is similar to the phenotype of BRCA1/2 mutant breast cancer; however, Ewing sarcoma cells exhibited robust BRCA1 expression and lacked BRCA1 mutations. Unexpectedly, BRCA1 overexpression restored homologous recombination in Ewing sarcoma cells, although this effect was abrogated when EWSR1 was depleted. Mechanistically, BRCA1 associated with transcriptional complexes at R-loops and was unable to go to sites of DNA repair, indicating a redistribution of BRCA1 protein in Ewing sarcoma cells that results in homologous recombination defects. Thus, Ewing sarcomas may phenocopy BRCA1-deficient tumors despite robust BRCA1 expression. Collectively, these findings reveal a mechanism by which homologous recombination is impaired in Ewing sarcoma, which may underlie the exquisite sensitivity of Ewing sarcoma to PARP inhibitors and other genotoxic agents.

Gorthi A, Romero JC, Loranc E, Cao L, Lawrence LA, Goodale E, et al. EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma. Nature 2018;555:387–91.

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