A novel role of DNA polymerase eta in modulating cellular sensitivity to chemotherapeutic agents

Mol Cancer Res. 2006 Apr;4(4):257-65. doi: 10.1158/1541-7786.MCR-05-0118.


Genetic defects in polymerase eta (pol eta; hRad30a gene) result in xeroderma pigmentosum variant syndrome (XP-V), and XP-V patients are sensitive to sunlight and highly prone to cancer development. Here, we show that pol eta plays a significant role in modulating cellular sensitivity to DNA-targeting anticancer agents. When compared with normal human fibroblast cells, pol eta-deficient cells derived from XP-V patients were 3-fold more sensitive to beta-d-arabinofuranosylcytosine, gemcitabine, or cis-diamminedichloroplatinum (cisplatin) single-agent treatments and at least 10-fold more sensitive to the gemcitabine/cisplatin combination treatment, a commonly used clinical regimen for treating a wide spectrum of cancers. Cellular and biochemical analyses strongly suggested that the higher sensitivity of XP-V cells to these agents was due to the inability of pol eta-deficient cells to help resume the DNA replication process paused by the gemcitabine/cisplatin-introduced DNA lesions. These results indicated that pol eta can play an important role in determining the cellular sensitivity to therapeutic agents. The findings not only illuminate pol eta as a potential pharmacologic target for developing new anticancer agents but also provide new directions for improving future chemotherapy regimen design considering the use of nucleoside analogues and cisplatin derivatives.

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • DNA / chemistry
  • DNA / drug effects*
  • DNA Replication / genetics
  • DNA-Directed DNA Polymerase / analysis
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / physiology*
  • Drug Resistance, Neoplasm / genetics*
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Humans
  • Nucleosides / chemistry
  • Nucleosides / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism
  • Xeroderma Pigmentosum / enzymology
  • Xeroderma Pigmentosum / genetics*


  • Antineoplastic Agents
  • Nucleosides
  • Proliferating Cell Nuclear Antigen
  • DNA
  • DNA-Directed DNA Polymerase
  • Rad30 protein