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
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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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