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

Nicholas C Turner, Christopher J Lord, Elizabeth Iorns, Rachel Brough, Sally Swift, Richard Elliott, Sydonia Rayter, Andrew N Tutt, Alan Ashworth

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1368-77
Number of pages10
JournalEMBO Journal
Issue number9
Publication statusPublished - 7 May 2008


  • Blotting, Western
  • Cell Cycle/drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 5/genetics
  • DNA Damage
  • DNA Repair
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide/pharmacology
  • Mitogen-Activated Protein Kinase 12/genetics
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases/metabolism
  • Protein-Serine-Threonine Kinases/genetics
  • RNA, Small Interfering/genetics
  • Transfection


Dive into the research topics of 'A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor'. Together they form a unique fingerprint.

Cite this