Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy

J. Yang, J. Parsons, N. H. Nicolay, S. Caporali, C. F. Harrington, R. Singh, D. Finch, S. Datri, P. B. Farmer, P. G. Johnston, W. G. McKenna, G. Dianov, R. A. Sharma

Research output: Contribution to journalArticle

Abstract

A significant proportion of human cancers overexpress DNA polymerase beta (Pol Β), the major DNA polymerase involved in base excision repair. The underlying mechanism and biological consequences of overexpression of this protein are unknown. We examined whether Pol Β, expressed at levels found in tumor cells, is involved in the repair of DNA damage induced by oxaliplatin treatment and whether the expression status of this protein alters the sensitivity of cells to oxaliplatin. DNA damage induced by oxaliplatin treatment of HCT116 and HT29 colon cancer cells was observed to be associated with the stabilization of Pol Β protein on chromatin. In comparison with HCT116 colon cancer cells, isogenic oxaliplatin-resistant (HCT-OR) cells were found to have higher constitutive levels of Pol Β protein, faster in vitro repair of a DNA substrate containing a single nucleotide gap and faster repair of 1,2-GG oxaliplatin adduct levels in cells. In HCT-OR cells, small interfering RNA knockdown of Pol Β delayed the repair of oxaliplatin-induced DNA damage. In a different model system, Pol Β-deficient fibroblasts were less able to repair 1,2-GG oxaliplatin adducts and were hypersensitive to oxaliplatin treatment compared with isogenic Pol Β-expressing cells. Consistent with previous studies, Pol Β-deficient mouse fibroblasts were not hypersensitive to cisplatin treatment. These data provide the first link between oxaliplatin sensitivity and DNA repair involving Pol Β. They demonstrate that Pol Β modulates the sensitivity of cells to oxaliplatin treatment.

Original languageEnglish
Pages (from-to)463-468
Number of pages6
JournalOncogene
Volume29
Issue number3
DOIs
Publication statusPublished - Jan 2010

Keywords

  • Colorectal cancer
  • DNA repair
  • Malignant melanoma

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Yang, J., Parsons, J., Nicolay, N. H., Caporali, S., Harrington, C. F., Singh, R., Finch, D., Datri, S., Farmer, P. B., Johnston, P. G., McKenna, W. G., Dianov, G., & Sharma, R. A. (2010). Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy. Oncogene, 29(3), 463-468. https://doi.org/10.1038/onc.2009.327