Dagg, Rebecca AZonderland, GijsLombardi, Emilia PuigRossetti, Giacomo GGroelly, Florian JBarroso, SoniaTacconi, Eliana M CWright, BenjaminLockstone, HelenAguilera, AndrésHalazonetis, Thanos DTarsounas, Madalena2023-02-092023-02-092021-08-13http://hdl.handle.net/10668/18372BRCA1 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/BRCA1 ProteinBRCA2 ProteinBreast NeoplasmsCell Line, TumorCell ProliferationCell SurvivalCells, CulturedCyclin-Dependent Kinase Inhibitor p21DNA DamageFemaleGene Expression ProfilingHeLa CellsHumansOncogenesOvarian NeoplasmsRNA-SeqTranscription, Geneticbeta Cateninresearch article34389725open access10.1038/s41467-021-25215-02041-1723PMC8363664https://www.nature.com/articles/s41467-021-25215-0.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363664/pdf