Translesion polymerase η is upregulated by cancer therapeutics and confers anticancer drug resistance

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Maja T Tomicic1, Dorthe Aasland1, Steffen C Naumann1

  • 1Department of Toxicology, University Medical Center Mainz, Mainz, Germany.

Cancer Research
|August 16, 2014
PubMed

Insights

Translesion polymerase eta (PolH) protects cancer cells from DNA crosslinking chemotherapy. This DNA repair mechanism promotes drug resistance and normal tissue protection against these agents.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • DNA repair mechanisms are critical in determining cancer cell sensitivity to chemotherapy.
  • Certain DNA repair genes can be induced by chemotherapeutics, contributing to drug resistance.

Purpose of the Study:

  • To identify DNA repair genes induced by DNA crosslinking agents in cancer cells.
  • To investigate the role of translesion polymerase eta (PolH) in cellular defense against interstrand crosslink (ICL)-inducing agents.

Main Methods:

  • A screen was conducted to identify repair genes induced by DNA crosslinking agents.
  • siRNA-mediated attenuation and overexpression of PolH were used to evaluate its role in drug sensitivity.
  • Host cell reactivation assays and γH2AX foci analysis measured ICL lesion repair.
  • PolH localization and DNA binding were assessed in drug-treated cells.

Main Results:

  • Translesion polymerase eta (PolH) was identified as a p53-regulated target induced by ICL-inducing agents (fotemustine, mafosfamide, lomustine) in various cancer and normal cells.
  • PolH induction conferred resistance to ICL-inducing agents in cancer cells, while PolH attenuation increased sensitivity.
  • PolH was found to be essential for efficient repair of ICL lesions and reduced γH2AX foci.
  • PolH accumulated in the nucleus of drug-treated cells and directly bound to damaged DNA.

Conclusions:

  • Translesion polymerase eta (PolH) plays a significant role in repairing interstrand crosslink lesions.
  • PolH functions as a mechanism of cancer drug resistance and normal tissue protection against ICL-inducing chemotherapeutics.

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