Assessment of Genotoxicity in Human Cells Exposed to Modulated Electromagnetic Fields of Wireless Communication Devices.

Modulated electromagnetic fields (wEMFs), as generated by modern communication technologies, have raised concerns about adverse health effects. The International Agency for Research on Cancer (IARC) classifies them as "possibly carcinogenic to humans" (Group 2B), yet, the underlying molecular mechanisms initiating and promoting tumorigenesis remain elusive. Here, we comprehensively assess the impact of technologically relevant wEMF modulations on the genome integrity of cultured human cells, investigating cell type-specificities as well as time- and dose-dependencies. Classical and advanced methodologies of genetic toxicology and DNA repair were applied, and key experiments were performed in two separate laboratories. Overall, we found no conclusive evidence for an induction of DNA damage nor for alterations of the DNA repair capacity in cells exposed to several wEMF modulations (i.e., GSM, UMTS, WiFi, and RFID). Previously reported observations of increased DNA damage after exposure of cells to GSM-modulated signals could not be reproduced. Experimental variables, presumably underlying the discrepant observations, were investigated and are discussed. On the basis of our data, we conclude that the possible carcinogenicity of wEMF modulations cannot be explained by an effect on genome integrity through direct DNA damage. However, we cannot exclude non-genotoxic, indirect, or secondary effects of wEMF exposure that may promote tumorigenesis in other ways.

Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil.

5-Fluorouracil (5-FU), a chemotherapeutic drug commonly used in cancer treatment, imbalances nucleotide pools, thereby favoring misincorporation of uracil and 5-FU into genomic DNA. The processing of these bases by DNA repair activities was proposed to cause DNA-directed cytotoxicity, but the underlying mechanisms have not been resolved. In this study, we investigated a possible role of thymine DNA glycosylase (TDG), one of four mammalian uracil DNA glycosylases (UDGs), in the cellular response to 5-FU. Using genetic and biochemical tools, we found that inactivation of TDG significantly increases resistance of both mouse and human cancer cells towards 5-FU. We show that excision of DNA-incorporated 5-FU by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling, and that the repair of 5-FU-induced DNA strand breaks is more efficient in the absence of TDG. Hence, excision of 5-FU by TDG, but not by other UDGs (UNG2 and SMUG1), prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity. The status of TDG expression in a cancer is therefore likely to determine its response to 5-FU-based chemotherapy.

Arginine methylation regulates DNA polymerase beta.

Alterations in DNA repair lead to genomic instability and higher risk of cancer. DNA base excision repair (BER) corrects damaged bases, apurinic sites, and single-strand DNA breaks. Here, a regulatory mechanism for DNA polymerase beta (Pol beta) is described. Pol beta was found to form a complex with the protein arginine methyltransferase 6 (PRMT6) and was specifically methylated in vitro and in vivo. Methylation of Pol beta by PRMT6 strongly stimulated DNA polymerase activity by enhancing DNA binding and processivity, while single nucleotide insertion and dRP-lyase activity were not affected. Two residues, R83 and R152, were identified in Pol beta as the sites of methylation by PRMT6. Genetic complementation of Pol beta knockout cells with R83/152K mutant revealed the importance of these residues for the cellular resistance to DNA alkylating agent. Based on our findings, we propose that PRMT6 plays a role as a regulator of BER.