dc.creator | Dagg, Rebecca A. | es |
dc.creator | Zonderland, Gijs | es |
dc.creator | Puig Lombardi, Emilia | es |
dc.creator | Rossetti, Giacomo G. | es |
dc.creator | Groelly, Florian J. | es |
dc.creator | Barroso Ceballos, Sonia Inés | es |
dc.creator | Tacconi, Eliana M. C. | es |
dc.creator | Wright, Benjamin | es |
dc.creator | Lockstone, Helen | es |
dc.creator | Aguilera López, Andrés | es |
dc.creator | Halazonetis, Thanos D. | es |
dc.creator | Tarsounas, Madalena | es |
dc.date.accessioned | 2021-09-01T14:35:08Z | |
dc.date.available | 2021-09-01T14:35:08Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | Dagg, R.A., Zonderland, G., Puig Lombardi, E., Rossetti, G.G., Groelly, F.J., Barroso Ceballos, S.I.,...,Tarsounas, M. (2021). A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells. Nature Communications, 12 (1), 4919. | |
dc.identifier.issn | 2041-1723 | es |
dc.identifier.uri | https://hdl.handle.net/11441/125269 | |
dc.description.abstract | BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. High-throughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/2 mutations are mutually exclusive in cancer, however the molecular mechanism underlying this incompatibility remains unknown. Here, we report that activation of β-catenin, an oncogene of the WNT signalling pathway, inhibits proliferation of BRCA1/2-deficient cells. RNA-seq analyses revealed β-catenin-induced discrete transcriptome alterations in BRCA2-deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21. This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. In addition, β-catenin activation accelerates replication fork progression in BRCA2-deficient cells, which is critically dependent on p21 downregulation. Importantly, we find that upregulated p21 expression is essential for the survival of BRCA2-deficient cells and tumours. Thus, our work demonstrates that β-catenin toxicity in cancer cells with compromised BRCA1/2 function is driven by transcriptional alterations that cause aberrant replication and inflict DNA damage. | es |
dc.description.sponsorship | European Research Council ERC2014 AdG669898 TARLOOP | es |
dc.description.sponsorship | Swiss National Science Foundation 182487 | es |
dc.description.sponsorship | European Union 722729, 886045 | es |
dc.format | application/pdf | es |
dc.format.extent | 17 p. | es |
dc.language.iso | eng | es |
dc.publisher | Springer Nature | es |
dc.relation.ispartof | Nature Communications, 12 (1), 4919. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.title | A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Genética | es |
dc.relation.projectID | ERC2014 AdG669898 TARLOOP | es |
dc.relation.projectID | 182487 | es |
dc.relation.projectID | 722729 | es |
dc.relation.projectID | 886045 | es |
dc.relation.publisherversion | https://doi.org/10.1038/s41467-021-25215-0 | es |
dc.identifier.doi | 10.1038/s41467-021-25215-0 | es |
dc.journaltitle | Nature Communications | es |
dc.publication.volumen | 12 | es |
dc.publication.issue | 1 | es |
dc.publication.initialPage | 4919 | es |