Transcription-Coupled and Global Genome Repair Differentially Influence UV-B-Induced Acute Skin Effects and Systemic Immunosuppression

Garssen, Johan; Steeg, Harry van; Gruijl, Frank de; Boer, Jan de; Horst, G.T.J. van der; Kranen, Henk van; Loveren, Henk Van; Dijk, Marjan A. van; Fluitman, Angelique; Weeda, Geert; Hoeijmakers, Jan H.J.

doi:10.4049/jimmunol.164.12.6199

Cited by 46 publications

(32 citation statements)

References 43 publications

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“…This is consistent with the formation of replication- and transcription-blocking DNA lesions (17). UVA treatment of cells containing DNA 6-TG generates 1 O 2 in DNA and this is also associated with severe inhibition of transcription and replication (6,10).…”

Section: Discussionsupporting

confidence: 88%

Guanine sulphinate is a major stable product of photochemical oxidation of DNA 6-thioguanine by UVA irradiation

Ren

Jeffs

et al. 2009

Nucleic Acids Research

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The DNA of patients taking the immunosuppressant and anticancer drugs azathioprine or 6-mercaptopurine contains 6-thioguanine (6-TG). The skin of these patients is selectively sensitive to ultraviolet A radiation (UVA) and they suffer an extremely high incidence of sunlight-induced skin cancer with long-term treatment. DNA 6-TG interacts with UVA to generate reactive oxygen species, which oxidize 6-TG to guanine sulphonate (GSO3). We suggested that GSO3 is formed via the reactive electrophilic intermediates, guanine sulphenate (GSO) and guanine sulphinate (GSO2). Here, GSO2 is identified as a significant and stable UVA photoproduct of free 6-TG, its 2′-deoxyribonucleoside, and DNA 6-TG. Mild chemical oxidation converts 6-TG into GSO2, which can be further oxidized to GSO3—a stable product that resists further reaction. In contrast, GSO2 is converted back to 6-TG under mild conditions. This suggests that cellular antioxidant defences might counteract the UVA-mediated photooxidation of DNA 6-TG at this intermediate step and ameliorate its biological effects. In agreement with this possibility, the antioxidant ascorbate protected DNA 6-TG against UVA oxidation and prevented the formation of GSO3.

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Section: Discussionsupporting

confidence: 88%

Guanine sulphinate is a major stable product of photochemical oxidation of DNA 6-thioguanine by UVA irradiation

Ren

Jeffs

et al. 2009

Nucleic Acids Research

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“…And also, it is well known that ROS may play a role in triggering apoptosis of UVA-irradiated cells (31–33). To investigate whether propolis prevents UVA-induced apoptosis of HaCaT cells by decreasing ROS formation, the level of intracellular ROS was evaluated by fluorescence microscopy with the oxidant-sensitive probe DCFH-DA (34).…”

Section: Resultsmentioning

confidence: 99%

Propolis Inhibits UVA-Induced Apoptosis of Human Keratinocyte HaCaT Cells by Scavenging ROS

Kim

Yoo

2016

ToxicolRes

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Propolis is a resinous material collected by honeybees from several plant sources. This research aimed at showing its protective effect against UVA-induced apoptosis of human keratinocyte HaCaT cells. Using Hoechst staining, it was demonstrated that propolis (5 and 10 μg/mL) significantly inhibited the apoptosis of HaCaT cells induced by UVA-irradiation. Propolis also showed the protective effect against loss of mitochondrial membrane potential induced by UVA-irradiaiton in HaCaT cells. Propolis also inhibited the expression of activated caspase-3 induced by UVA-irradiation. To investigate the role of ROS in UVA-induced apoptosis and protection by propolis, the generation of ROS was determined in cells. The results showed that the generation of ROS was markedly reduced in cells pretreated with propolis. Consequently, propolis protected human keratinocyte HaCaT cells against UVA-induced apoptosis, which might be related to the reduction of ROS generation by UVA-irradiation.

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“…For instance, complete NER abrogation, (e.g., Xpa knockout mice), strongly increases the susceptibility to UV-induced systemic immunosuppression (13,29). However, whereas in mice lacking only TC-NER (e.g., Csb mutant mice) or GG-NER (e.g., XPC mice) systemic immunosuppression is substantially reduced, local immunosuppression correlates with local Langerhans cell depletion and occurs at lower UV doses in TC-NER-deficient mice (Csb and Xpa mice) (23).…”

Section: Vol 26 2006 Role Of Basal Keratinocytes In Uv-induced Skinmentioning

confidence: 99%

Differential Role of Basal Keratinocytes in UV-Induced Immunosuppression and Skin Cancer

Jans

Garinis

Schul

et al. 2006

Molecular and Cellular Biology

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Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type specificity to the harmful biological effects of UV exposure remains currently unclear. Using a series of photolyase-transgenic mice to ubiquitously remove either CPDs or 6-4PPs from all cells in the mouse skin or selectively from basal keratinocytes, we show that the majority of UV-induced acute effects to require the presence of CPDs in basal keratinocytes in the mouse skin. At the fundamental level of gene expression, CPDs induce the expression of genes associated with repair and recombinational processing of DNA damage, as well as apoptosis and a response to stress. At the organismal level, photolyase-mediated removal of CPDs, but not 6-4PPs, from the genome of only basal keratinocytes substantially diminishes the incidence of skin tumors; however, it does not affect the UVB-mediated immunosuppression. Taken together, these findings reveal a differential role of basal keratinocytes in these processes, providing novel insights into the skin's acute and chronic responses to UV in a lesion-and cell-type-specific manner.Exposure to UV light has undesired health consequences with increasing impact; apart from acute effects (e.g., sunburn), skin tumors are considered a major threat, demonstrated by their increasing incidence in white populations, due to altered life style and the erosion of the protecting ozone layer (1, 43). Besides the ability of RNA (20, 21) and proteins (5) to absorb light at the UV wavelength, our recent findings have unequivocally pointed to DNA as the biologically most relevant target of UV radiation (12,22,35). UV induces the formation of major dimer configurations, namely the cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs), generated by covalent bonds between two adjacent pyrimidines, that interfere with biological processes (e.g., transcription and replication) critical for cell viability (28).To recognize and remove effectively the wide range of hazardous DNA lesions, mammalian cells employ a resourceful battery of DNA repair systems (10,

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Transcription-Coupled and Global Genome Repair Differentially Influence UV-B-Induced Acute Skin Effects and Systemic Immunosuppression

Cited by 46 publications

References 43 publications

Guanine sulphinate is a major stable product of photochemical oxidation of DNA 6-thioguanine by UVA irradiation

Guanine sulphinate is a major stable product of photochemical oxidation of DNA 6-thioguanine by UVA irradiation

Propolis Inhibits UVA-Induced Apoptosis of Human Keratinocyte HaCaT Cells by Scavenging ROS

Differential Role of Basal Keratinocytes in UV-Induced Immunosuppression and Skin Cancer

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