The nuclear aryl hydocarbon receptor is involved in regulation of DNA repair and cell survival following treatment with ionizing radiation.

In the present study, we explored the role of the aryl hydrocarbon receptor (AhR) for γ-H2AX associated DNA repair in response to treatment with ionizing radiation. Ionizing radiation was able to stabilize AhR protein and to induce a nuclear translocation in a similar way as described for exposure to aromatic hydrocarbons. A comparable AhR protein stabilization was obtained by treatment with hydroxyl-nonenal-generated by radiation-induced lipid peroxidation. AhR knockdown resulted in significant radio-sensitization of both A549- and HaCaT cells. Under these conditions an increased amount of residual γ-H2AX foci and a delayed decline of γ-H2AX foci was observed. Knockdown of the co-activator ARNT, which is essential for transcriptional activation of AhR target genes, reduced AhR-dependent CYP1A expression in response to irradiation, but was without effect on the amount of residual γ-H2AX foci. Nuclear AhR was found in complex with γ-H2AX, DNA-PK, ATM and Lamin A. AhR and γ-H2AX form together nuclear foci, which disappear during DNA repair. Presence of nuclear AhR protein is associated with ATM activation and chromatin relaxation indicated by acetylation of histone H3. Taken together, we could show, that beyond the function as a transcription factor the nuclear AhR is involved in the regulation of DNA repair. Reduction of nuclear AhR inhibits DNA-double stand repair and radiosensitizes cells. First hints for its molecular mechanism suggest a role during ATM activation and chromatin relaxation, both essential for DNA repair.

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1.

Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27(KIP1) and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer.

[Studies on the physiological specialization of Erysiphe graminis DC : IV. The host plants of cocksfoot mildew]. / Untersuchungen zur physiologischen Spezialisierung von Erysiphe graminis DC : IV. Der Wirtspflanzenbereich des Dactylis-Mehltaus.

In the described experiments the interaction of 460 grass species with a mildew population obtained from Dactylis glomerata L. 'Motterwitzer' was examined. 420 species remained free of symptoms, while 40 species were susceptible. The most susceptible ones were Dactylis aschersoniana Graebner, Dactylis glomerata L., Dactylis glomerata spp. aschersoniana (Graebn.) Thell., and Dactylis polygama Horvat, but all showed differences in their behaviour. The unexpectedly low susceptibility of Dactylis woronowii Ovcz. should be examined again. Three grass species Bouteloua hirsuta Lag., Danthonia provinzialis DC., and Sesleria latifolia (Adam) Degen were also highly susceptible to cocksfoot mildew, while on wild grasses of the species Agropyron, Bromus, Festuca, Mibora, Poa, and Sesleria only few symptoms could be seen. Among cereals only barley could be infected by cocksfoot mildew. Not only in the wild form of Dactylis glomerata L. but also in the cultivated variety 'Motterwitzer', above 10% were found to be free from infection. Therefore the breeding of resistant varieties of Dactylis glomerata L. seems to be feasible.

[Studies on the physiological specialization of Erysiphe graminis DC : V. The reaction of important fodder grasses cultivated in the GDR against some races of cereal mildew]. / Untersuchungen zur physiologischen spezialisierung von Erysiphe graminis DC : V. Das Verhalten wichtiger in der DDR angebauter Futtergräser gegenüber einigen Rassen des Getreidemehltaus.

In an examination of the susceptibility of 27 fodder grass varieties cultivated in the GDR to 14 races of barley mildew, 9 races of wheat mildew and 1 population of rye mildew no infections were obtained. Since the races used represented the whole range of pathogenicity of the known races of cereal mildew, it may be assumed that under natural conditions cereal mildew does not cause any infection in the examined varieties of forage grasses.