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Article

  • The EMBO Journal (2008) 27, 1368 - 1377
  • doi:10.1038/emboj.2008.61

Published online: 3 April 2008

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

  1. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
  2. 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

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