Protective role of Puralpha to cisplatin

Cancer Biol Ther. 2008 Dec;7(12):1926-35. doi: 10.4161/cbt.7.12.6938. Epub 2008 Dec 8.

Abstract

Background: The nucleic acid-binding protein Puralpha is involved at stalled DNA replication forks, in double-strand break (DSB) DNA repair and the cellular response to DNA replication stress. Puralpha also regulates homologous recombination-directed DNA repair (HRR).

Results: Cells lacking Puralpha showed enhanced sensitivity to cisplatin as evaluated by assays for cell viability and cell clonogenicity. This was seen both in Puralpha-negative MEFs and in human glioblastoma cells treated with siRNA directed against Puralpha. MEFs lacking Puralpha also showed enhanced H2AX phosphorylation in response to cisplatin. Repair of a reporter plasmid that had been treated with cisplatin was decreased in a reactivation assay using Puralpha-negative MEFs and the capacity of nuclear extracts from Puralpha-negative MEFs to perform non-homologous end-joining in vitro was also impaired.

Methods: We investigated the effects of the DNA damage-inducing cancer chemotherapeutic agent cisplatin on mouse embryo fibroblasts (MEFs) from PURA(-/-) knockout mice that lack Puralpha.

Conclusions: Puralpha has a role in the cellular response to cisplatin-induced DNA damage and may provide new therapeutic modalities for cisplatin-resistant tumors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Survival / drug effects
  • Cisplatin / adverse effects
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use*
  • Colony-Forming Units Assay
  • DNA Damage*
  • DNA Repair / physiology*
  • DNA Replication / physiology*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / physiology*
  • DNA-Binding Proteins / therapeutic use
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Transcription Factors / deficiency
  • Transcription Factors / physiology*
  • Transcription Factors / therapeutic use

Substances

  • DNA-Binding Proteins
  • PURA protein, human
  • Transcription Factors
  • Hydrogen Peroxide
  • Cisplatin