title: Translesion polymerase η is upregulated by cancer therapeutics and confers anticancer drug resistance.
abstract: DNA repair processes are a key determinant of the sensitivity of cancer cells to DNA-damaging chemotherapeutics, which may induce certain repair genes as a mechanism to promote resistance. Here, we report the results of a screen for repair genes induced in cancer cells treated with DNA crosslinking agents, which identified the translesion polymerase η (PolH) as a p53-regulated target acting as one defense against interstrand crosslink (ICL)-inducing agents. PolH was induced by fotemustine, mafosfamide, and lomustine in breast cancer, glioma, and melanoma cells in vitro and in vivo, with similar inductions observed in normal cells such as lymphocytes and diploid fibroblasts. PolH contributions to the protection against ICL-inducing agents were evaluated by its siRNA-mediated attenuation in cells, which elevated sensitivity to these drugs in all tumor cell models. Conversely, PolH overexpression protected cancer cells against these drugs. PolH attenuation reduced repair of ICL lesions as measured by host cell reactivation assays and enhanced persistence of γH2AX foci. Moreover, we observed a strong accumulation of PolH in the nucleus of drug-treated cells along with direct binding to damaged DNA. Taken together, our findings implicated PolH in ICL repair as a mechanism of cancer drug resistance and normal tissue protection.
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Tomicic
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Aasland
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Steffen C
authors.initials: SC
authors.lastname: Naumann
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Meise
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Barckhausen
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany. mchristm@uni-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Christmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015854:Up-Regulation; D000099270:Y-Family DNA Polymerases
chemical_list: D000970:Antineoplastic Agents; D004259:DNA-Directed DNA Polymerase; D016159:Tumor Suppressor Protein p53; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases