A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor |
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Authors: | Turner Nicholas C Lord Christopher J Iorns Elizabeth Brough Rachel Swift Sally Elliott Richard Rayter Sydonia Tutt Andrew N Ashworth Alan |
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Affiliation: | The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. |
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Abstract: | Inhibitors of poly (ADP-ribose)-polymerase-1 (PARP) are highly lethal to cells with deficiencies in BRCA1, BRCA2 or other components of the homologous recombination pathway. This has led to PARP inhibitors entering clinical trials as a potential therapy for cancer in carriers of BRCA1 and BRCA2 mutations. To discover new determinants of sensitivity to these drugs, we performed a PARP-inhibitor synthetic lethal short interfering RNA (siRNA) screen. We identified a number of kinases whose silencing strongly sensitised to PARP inhibitor, including cyclin-dependent kinase 5 (CDK5), MAPK12, PLK3, PNKP, STK22c and STK36. How CDK5 silencing mediates sensitivity was investigated. Previously, CDK5 has been suggested to be active only in a neuronal context, but here we show that CDK5 is required in non-neuronal cells for the DNA-damage response and, in particular, intra-S and G(2)/M cell-cycle checkpoints. These results highlight the potential of synthetic lethal siRNA screens with chemical inhibitors to define new determinants of sensitivity and potential therapeutic targets. |
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Keywords: | CDK5 cell cycle DNA repair poly(ADP)ribose polymerase RNAi screen |
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