Article
- The EMBO Journal (2008) 27, 1368 - 1377
- doi:10.1038/emboj.2008.61
Published online: 3 April 2008
Subject Category:
A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor
Nicholas C Turner1, Christopher J Lord1, Elizabeth Iorns1, Rachel Brough1, Sally Swift1, Richard Elliott1, Sydonia Rayter1, Andrew N Tutt1,2 and Alan Ashworth1
- The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
- Breakthrough Breast Cancer Research Unit, King's College London School of Medicine, Guy's Hospital, London, UK
Correspondence to:
Alan Ashworth, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. Tel.: +44 0 20 7153 5333; Fax: +44 0 20 7153 5340; E-mail: alan.ashworth@icr.ac.uk
Received 10 September 2007; Accepted 4 March 2008
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.
Keywords:
- CDK5,
- cell cycle,
- DNA repair,
- poly(ADP)ribose polymerase,
- RNAi screen
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