Ewing sarcoma is an aggressive paediatric 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 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 tumours.
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Gene Expression Omnibus
We thank F. Chedin for the DRIP–seq protocol and genome-wide restriction enzyme sites file, and R. Crouch, J. Stark and Y. Shiio for plasmids. We are grateful to the UTH-SA/Cancer Center Sequencing core and the Histology & Immunohistochemistry Core at UTH-SA. This work was funded by the NIH (K22ES012264, 1R15ES019128, 1R01CA152063), a Voelcker Fund Young Investigator Award and CPRIT (RP150445) to A.J.R.B.; CPRIT (RP101491), a Translational Science Training Across Disciplines Scholarship (UTHSA) and an NCI postdoctoral training grant (T32CA148724) to A.G.; CPRIT (RP140105) to J.C.R.; NIH (P30CA054174) to Mays Cancer Center; NCI (R01CA204915) and Curing Kids Cancer to K.S.; NIH CTSA (1UL1RR025767-01, P30CA054174) and CPRIT (RP120685-C2) to Y.C.; NIH (1R01CA140394) to S.L.L. and NIH (1R01CA134605) to E.R.L.
Extended data figures
Extended data tables
Damage-induced changes in gene expression between IMR90 and EwS cell lines. Supplementary Table 1.1 contains a list of genes that are at least two-fold altered upon etoposide treatment in IMR90 but not in EwS cell lines. The criterion for evaluation of EwS cells was as follows: genes that were upregulated at least 2-fold in IMR90 but less than 0-fold (no change or downregulated) in EwS and vice versa. Supplementary Table 1.2 contains a list of genes that are at least two-fold altered upon etoposide treatment in EwScell lines but not in IMR90. The criterion for evaluation is as follows: genes that were upregulated at least 2-fold in EwS but less than 0-fold (no change or downregulated) in IMR90 and vice versa. Supplementary Table 1.3 contains a list of genes that were similarly altered (minimum 2-fold change) by gene expression in response to damage between IMR90 and EwS.
This table shows the top 5% hits in the Drosophila kc167 RNAi screens. Data was collected as percent survival upon damage induction (3 days) for each RNAi. The loci that mapped to NCBI gene IDs are listed
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Nature Reviews Disease Primers (2018)