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

Yih Wen Chen, James E. Cleaver, Fumio Hanaoka, Ching Fang Chang, Kai Ming Chou

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Genetic defects in polymerase η (pol η; 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 η plays a significant role in modulating cellular sensitivity to DNA-targeting anticancer agents. When compared with normal human fibroblast cells, pol η-deficient cells derived from XP-V patients were 3-fold more sensitive to β-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 η-deficient cells to help resume the DNA replication process paused by the gemcitabine/cisplatin-introduced DNA lesions. These results indicated that pol η can play an important role in determining the cellular sensitivity to therapeutic agents. The findings not only illuminate pol η 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.

Original languageEnglish (US)
Pages (from-to)257-265
Number of pages9
JournalMolecular Cancer Research
Volume4
Issue number4
DOIs
StatePublished - Apr 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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