A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells

Rebecca A. Dagg, Gijs Zonderland, Emilia Puig Lombardi, Giacomo G. Rossetti, Florian J. Groelly, Sonia Barroso, Eliana M. C. Tacconi, Benjamin Wright, Helen Lockstone, Andrés Aguilera, Thanos D. Halazonetis and Madalena Tarsounas ()
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Rebecca A. Dagg: University of Oxford
Gijs Zonderland: University of Oxford
Emilia Puig Lombardi: University of Oxford
Giacomo G. Rossetti: University of Geneva
Florian J. Groelly: University of Oxford
Sonia Barroso: Universidad de Sevilla-Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide
Eliana M. C. Tacconi: University of Oxford
Benjamin Wright: University of Oxford
Helen Lockstone: University of Oxford
Andrés Aguilera: Universidad de Sevilla-Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide
Thanos D. Halazonetis: University of Geneva
Madalena Tarsounas: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25215-0

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