EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma.

Abstract

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.

• Authors: 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
• Journal: Nature (Nature) Vol. 555 Issue 7696 Pg. 387-391 (03 15 2018) ISSN: 1476-4687 [Electronic] England
• PMID: 29513652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• EWS-FLI fusion protein
• Oncogene Proteins, Fusion
• Proto-Oncogene Protein c-fli-1
• RNA-Binding Protein EWS

Topics

• BRCA1 Protein (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• DNA Damage
• Gene Expression Regulation, Neoplastic
• Humans
• Nucleic Acid Conformation
• Oncogene Proteins, Fusion (genetics, metabolism)
• Proto-Oncogene Protein c-fli-1 (genetics, metabolism)
• RNA-Binding Protein EWS (genetics, metabolism)
• Recombinational DNA Repair
• Sarcoma, Ewing (genetics, metabolism)
• Transcription, Genetic