|A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. Turner et al. (2008)||Combinatorial effect with Poly (ADP‐ribose)‐polymerase‐1 (PARP)||Viability||CAL51||H. sapiens|
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.
Stable Id: GR00114-A
Screen title: Combinatorial effect with Poly (ADP‐ribose)‐polymerase‐1 (PARP)
Screen type: Cell-based
Species: Homo sapiens
Biosource: Cell line
Library: Dharmacon, siARRAY SMARTpool
Reagent type: siRNA
Score type: Z-score
Cutoff: <= -3
Notes: Growth rates (%) for vehicle-alone experiments are given in the comment field.