Skip to content
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. 1368-1377

  • 158

    Readers

    Mendeley users who have this article in their library.
  • 204

    Citations

    Citations of this article.
  • N/A

    Views

    ScienceDirect users who have downloaded this article.
Sign in to save reference

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.

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Get full text

Authors

  • Nicholas C Turner

  • Christopher J Lord

  • Elizabeth Iorns

  • Rachel Brough

  • Sally Swift

  • Richard Elliott

Cite this document

Choose a citation style from the tabs below