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EMBO J. 2008 May 7;27(9):1368-77. doi: 10.1038/emboj.2008.61. Epub 2008 Apr 3.

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

Author information

  • 1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

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.

PMID:
18388863
[PubMed - indexed for MEDLINE]
PMCID:
PMC2374839
Free PMC Article

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