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 protein. 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.

中文翻译：

---

EWS-FLI1 增加转录以引起 R 环并阻止尤文肉瘤中的 BRCA1 修复

尤文肉瘤是一种侵袭性小儿骨和软组织癌症。它是由染色体易位引起的，主要是 t(11;22)(q24:q12)，它将组成型表达的 EWSR1 蛋白的 N 端反式激活域与很少表达的 FLI1 蛋白的 C 端 DNA 结合域融合。尤文肉瘤对依托泊苷等遗传毒性药物高度敏感，但这种敏感性的潜在分子基础尚不清楚。在这里，我们显示尤文肉瘤细胞在损伤诱导的转录、R 环的积累和复制应激增加的调节方面表现出改变。此外，由于 BRCA1 和延伸转录机制之间的相互作用增强，尤文肉瘤中的同源重组受损。最后，我们揭示了 EWSR1 在对损伤、抑制 R 环和促进同源重组的转录反应中的作用。我们的研究结果提高了目前对 EWSR1 功能的理解，阐明了尤文肉瘤对化疗（包括 PARP1 抑制剂）敏感性的机制基础，并突出了一类 BRCA 缺陷样肿瘤。