Artículo
A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells
Autor/es | Dagg, Rebecca A.
Zonderland, Gijs Puig Lombardi, Emilia Rossetti, Giacomo G. Groelly, Florian J. Barroso Ceballos, Sonia Inés Tacconi, Eliana M. C. Wright, Benjamin Lockstone, Helen Aguilera López, Andrés Halazonetis, Thanos D. Tarsounas, Madalena |
Departamento | Universidad de Sevilla. Departamento de Genética |
Fecha de publicación | 2021 |
Fecha de depósito | 2021-09-01 |
Publicado en |
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Resumen | 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, ... 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. |
Identificador del proyecto | ERC2014 AdG669898 TARLOOP
182487 722729 886045 |
Cita | 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. |
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