Loss of POLE3-POLE4 unleashes replicative gap accumulation upon treatment with PARP inhibitors
Bethany Rebekah Hill,
Meryem Ozgencil,
Lauryn Buckley-Benbow,
Sophie Louise Pamela Skingsley,
Danielle Tomlinson,
Carmen Ortueta Eizmendi,
Alessandro Agnarelli,
Roberto Bellelli
Affiliations
Bethany Rebekah Hill
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
Meryem Ozgencil
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
Lauryn Buckley-Benbow
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
Sophie Louise Pamela Skingsley
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
Danielle Tomlinson
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
Carmen Ortueta Eizmendi
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
Alessandro Agnarelli
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
Roberto Bellelli
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK; Corresponding author
Summary: The advent of PARP inhibitors (PARPis) has profoundly changed the treatment landscape of BRCA1/BRCA2-mutated cancers. Despite this, the development of resistance to these compounds has become a major challenge. Hence, a detailed understanding of the mechanisms underlying PARPi sensitivity is crucially needed. Here, we show that loss of the POLE3-POLE4 subunits of DNA polymerase epsilon (Polε) strongly sensitizes cancer cells to PARPis in a Polε level-independent manner. Loss of POLE3-POLE4 is not associated with defective RAD51 foci formation, excluding a major defect in homologous recombination. On the contrary, treatment with PARPis triggers replicative gap accumulation in POLE3-POLE4 knockout (KO) cells in a PRIMPOL-dependent manner. In addition to this, the loss of POLE3-POLE4 further sensitizes BRCA1-silenced cells to PARPis. Importantly, the knockdown of 53BP1 does not rescue PARPi sensitivity in POLE3-POLE4 KO cells, bypassing a common PARPi resistance mechanism and outlining a potential strategy to sensitize cancer cells to PARPis.
