Journal article

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

Turner N, Lord C, Iorns E, Brough R, Swift S, Elliott R, Rayter S, Tutt A, Ashworth A ...see all

The EMBO journal, vol. 27, issue 9 (2008) pp. 1368-77

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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.

Author-supplied keywords

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

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Authors

  • Nicholas C Turner

  • Christopher J Lord

  • Elizabeth Iorns

  • Rachel Brough

  • Sally Swift

  • Richard Elliott

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