00085472can140953-sup-129100_1_supp_0_nscplw.pdf (95.86 kB)
Supplementary Figure Legend from Translesion Polymerase η Is Upregulated by Cancer Therapeutics and Confers Anticancer Drug Resistance
journal contributionposted on 2023-03-30, 22:50 authored by Maja T. Tomicic, Dorthe Aasland, Steffen C. Naumann, Ruth Meise, Christina Barckhausen, Bernd Kaina, Markus Christmann
Supplementary Figure Legend
ARTICLE ABSTRACTDNA 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. Cancer Res; 74(19); 5585–96. ©2014 AACR.
CarcinogenesisDNA damage and repairDrug MechanismsCellular responses to anticancer drugsModulation of DNA repairp53 and anticancer drug actionDrug ResistanceRegulation of gene expression in drug resistanceGene RegulationInducible gene expressionMechanisms of transcriptionOncogenes & Tumor Suppressorsp53Skin Cancers