A novel role of DNA polymerase eta in modulating cellular sensitivity to chemotherapeutic agents.
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.
Chen
Yih-wen
YW
Department of Cell Biology and Neuroscience, University of South Alabama, 307 North University Boulevard, MSB 2350, Mobile, AL 36688, USA.
Cleaver
James E
JE
Hanaoka
Fumio
F
Chang
Ching-fang
CF
Chou
Kai-ming
KM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004261:DNA Replication / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D014983:Xeroderma Pigmentosum / Q000201:enzymology / Q000235:genetics*; D000099270:Y-Family DNA Polymerases
D000970:Antineoplastic Agents; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D009705:Nucleosides; D018809:Proliferating Cell Nuclear Antigen; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases