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Nature. 2018 Mar 15;555(7696):387-391. doi: 10.1038/nature25748. Epub 2018 Mar 7.

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

Author information

1
Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, Texas 78229, USA.
2
Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, Texas 78229, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
4
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
5
Departments of Oncology and Pediatrics, Georgetown University, Washington DC 20057, USA.
6
Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
7
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
8
Mays Cancer Center, University of Texas Health at San Antonio, Texas 78229, USA.
9
Department of Epidemiology and Biostatistics, University of Texas Health at San Antonio, San Antonio, Texas 78229, USA.

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.

PMID:
29513652
DOI:
10.1038/nature25748
[Indexed for MEDLINE]

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