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- Title
A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor.
- Authors
Turner, Nicholas C; Lord, Christopher J; Iorns, Elizabeth; Brough, Rachel; Swift, Sally; Elliott, Richard; Rayter, Sydonia; Tutt, Andrew N; Ashworth, Alan
- 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 G2/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.
- Subjects
POLY(ADP-ribose) polymerase; SMALL interfering RNA; GENOMES; CYCLIN-dependent kinases; CHEMICAL inhibitors; CELLS; CLINICAL trials; CANCER
- Publication
EMBO Journal, 2008, Vol 27, Issue 9, p1368
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/emboj.2008.61