%0 Journal Article
%A Dagg, Rebecca A
%A Zonderland, Gijs
%A Lombardi, Emilia Puig
%A Rossetti, Giacomo G
%A Groelly, Florian J
%A Barroso, Sonia
%A Tacconi, Eliana M C
%A Wright, Benjamin
%A Lockstone, Helen
%A Aguilera, Andrés
%A Halazonetis, Thanos D
%A Tarsounas, Madalena
%T A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells.
%D 2021
%U http://hdl.handle.net/10668/18372
%X 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.
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