RAD21 is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress.
Genes Dev
; 35(7-8): 556-572, 2021 04 01.
Article
em En
| MEDLINE
| ID: mdl-33766983
ABSTRACT
Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why â¼50% 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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MEDLINE
Assunto principal:
Sarcoma de Ewing
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Estresse Fisiológico
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Trissomia
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Proteínas de Ciclo Celular
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Proteínas de Ligação a DNA
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Carcinogênese
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article