A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor

作者：Turner Nicholas C; Lord Christopher J; Iorns Elizabeth; Brough Rachel; Swift Sally; Elliott Richard; Rayter Sydonia; Tutt Andrew N; Ashworth Alan^*

来源：The EMBO Journal, 2008, 27(9): 1368-1377.

DOI：10.1038/emboj.2008.61

• CDK5
• cell cycle
• DNA repair
• poly(ADP) ribose
• polymerase
• RNAi screen

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.

• 出版日期2008-5-7