RAD21 is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress
- Xiaofeng A. Su1,
- Duanduan Ma2,
- James V. Parsons3,
- John M. Replogle1,
- James F. Amatruda4,5,
- Charles A. Whittaker2,
- Kimberly Stegmaier6,7 and
- Angelika Amon1
- 1David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 2The Barbara K. Ostrom (1978) Bioinformatics and Computing Facility, Swanson Biotechnology Center, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 4Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 5Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 6Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA;
- 7The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA
- Corresponding author: allensu{at}mit.edu
Abstract
Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why ∼50% of Ewing sarcomas, driven by the EWS-FLI1 fusion oncogene, harbor chromosome 8 gains. Expression of the EWS-FLI1 fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates EWS-FLI1-induced replication stress through gain of a copy of RAD21. Low-level ectopic expression of RAD21 is sufficient to dampen replication stress and improve proliferation in EWS-FLI1-expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that RAD21 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.345454.120.
- Received October 4, 2020.
- Accepted February 25, 2021.
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