Cyclobutane pyrimidine dimer formation is a molecular trigger for solar-simulated ultraviolet radiation-induced suppression of memory immunity in humans

Kuchel, Johanna M.; Barnetson, R S; Halliday, Gary M.

doi:10.1039/b504068j

Cited by 74 publications

(37 citation statements)

References 31 publications

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“…The observation that UVA may induce the formation of CPDs also may have some mechanistic implications into its immunosuppressive properties. Indeed, DNA damage has been shown to be involved in UVA-induced immunosuppression (58). The likely biological significance of the UVA-induced CPDs makes necessary additional work to definitively establish the underlying mechanism of formation.…”

Section: Resultsmentioning

confidence: 99%

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Mouret

Baudouin

Charvéron

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

585

569

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Solar UV radiation is the most important environmental factor involved in the pathogenesis of skin cancers. The well known genotoxic properties of UVB radiation (290 -320 nm) mostly involve bipyrimidine DNA photoproducts. In contrast, the contribution of more-abundant UVA radiation (320 -400 nm) that are not directly absorbed by DNA remains poorly understood in skin. Using a highly accurate and quantitative assay based on HPLC coupled with tandem mass spectrometry, we determined the type and the yield of formation of DNA damage in whole human skin exposed to UVB or UVA. Cyclobutane pyrimidine dimers, a typical UVBinduced DNA damage, were found to be produced in significant yield also in whole human skin exposed to UVA through a mechanism different from that triggered by UVB. Moreover, the latter class of photoproducts is produced in a larger amount than 8-oxo-7,8-dihydro-2-deoxyguanosine, the most common oxidatively generated lesion, in human skin. Strikingly, the rate of removal of UVA-generated cyclobutane pyrimidine dimers was lower than those produced by UVB irradiation of skin. Finally, we compared the formation yields of DNA damage in whole skin with those determined in primary cultures of keratinocytes isolated from the same donors. We thus showed that human skin efficiently protects against UVB-induced DNA lesions, whereas very weak protection is afforded against UVA. These observations emphasize the likely role played by the UVA-induced DNA damage in skin carcinogenesis and should have consequences for photoprotection strategies.carcinogenesis ͉ DNA damage ͉ mutagenesis ͉ oxidative stress ͉ DNA repair O ccurrence of skin cancers, which mostly arise from exposure to solar UV radiation, has constantly increased in the recent years due to changes in life habits. Harmful effects of UV radiation are mostly associated with both direct and indirect photoinduced damage to DNA (1) that can lead to the induction of mutations. The chemical nature and the formation efficiency of the DNA lesions greatly depend on the wavelength of the incident photons. UVB radiation (290-320 nm), the most energetic mutagenic and carcinogenic component of solar radiation, is directly absorbed by DNA, giving rise to dimeric photoproducts between adjacent pyrimidine bases. Two types of these bulky modifications are produced, namely cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (1). Evidence for the involvement of these lesions in photocarcinogenesis is provided by the high proportion of p53 mutations (TC to TT or CC to TT transitions) detected at bipyrimidine sites in skin tumors (2-4).UVA radiation (320-400 nm), the other component of terrestrial UV radiation, is mutagenic in cultured cells (5, 6) and induces skin tumors in mice (7,8). In addition, UVA has been shown to be involved in immunosuppression (9) and is suspected to play a major role in the induction of melanoma (10, 11), the most severe type of skin cancers. Consequently, the carcinogenic properties of UVA have become a matter of concern...

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Section: Resultsmentioning

confidence: 99%

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Mouret

Baudouin

Charvéron

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

585

569

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“…As well as being pro-mutagenic, reactive nitrogen species also have been reported to inhibit DNA repair [41,42] and conversely nitric oxide synthase inhibitors enhance DNA repair mechanisms [43].…”

Section: Uv-induced Dna Damage and Repairmentioning

confidence: 99%

Sunlight Protection by Vitamin D Compounds

et al. 2011

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“…Ebenso sind Mutationen in NOTCH1/NOTCH2 und SMO [16] [20]. Eine weitere molekulare Zielstruktur der UV-Strahlung, die zu Immunsuppression führt, ist die DNA [21]. Auf zellulärer Ebene sind -aufgrund ihrer Lage in den oberen Hautschichten -epidermale Keratinozyten und LZ direkte Zielstrukturen von UVStrahlen.…”

Section: Uv-induzierte Genmutationen Die Zu Aktinischer Keratose Undunclassified

Lichtbedingte Schädigungen: Vorboten von aktinischer Keratose und frühem Plattenepithelkarzinom

et al. 2015

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Ultraviolette (UV-)Strahlung ist aller Wahrscheinlichkeit nach ein treibender Faktor für die Entstehung von Hauttumoren und die Progression von aktinischer Keratose zum Plattenepithelkarzinom. Lichtbedingte Schädigungen treten auf vielen verschiedenen Ebenen auf. UV-Strahlen verursachen Schäden an zahlreichen Zellbestandteilen - darunter Lipide, Proteine und DNA -, die wahrscheinlich allesamt zu UV-bedingtem Hautkrebs beitragen. Zwei biologische Ereignisse, die letztlich durch eine solche Lichtschädigung hervorgerufen werden, sind Mutationen in den Genen, die für die Steuerung der Zellteilung, -differenzierung und -wanderung verantwortlich sind, sowie Immunsuppression. Wenn lichtbedingte DNA-Schäden vor der Zellteilung nicht repariert werden, kann dies zum Einbau eines fehlerhaften Nukleotids in neu synthetisierte DNA führen. Mutationen in kritischen Genen tragen zur Karzinogenese bei. Eine lichtbedingte Schädigung von Proteinen, die z.B. an der DNA-Reparatur beteiligt sind, oder von Proteinen oder Lipiden, die an zellulärer Signalübermittlung partizipieren, kann diese Reparaturmechanismen behindern und zur Mutagenese beitragen. Mutationen in Schlüsselgenen wie TP53, BRM, PTCH1 oder HRAS können zur kutanen Karzinogenese beitragen. Durch UV-Strahlung wird auch die Immunabwehr beeinträchtigt. Lichtbedingte Schädigungen von DNA und Signallipiden sowie andere molekulare Veränderungen sind schädlich für wichtige Zellen der Immunregulation. Lichtgeschädigte dendritische Zellen und Mastzellen mit verändertem Verhalten führen zur Aktivierung von regulatorischen T- und B-Zellen; diese unterdrücken die Immunreaktion auf die Proteinprodukte UV-mutierter Gene. Dadurch kann das Immunsystem seine Schutzfunktion, mutierte Zellen zu zerstören, nicht mehr ausüben, und die transformierten Zellen können zu Hautkrebs progredieren. UV-Strahlung scheint bei jedem dieser Schritte eine zentrale Rolle zu spielen, daher sind Anzeichen lichtbedingter Schädigungen als Vorboten der Entstehung von Hautkrebs aufzufassen.

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Cyclobutane pyrimidine dimer formation is a molecular trigger for solar-simulated ultraviolet radiation-induced suppression of memory immunity in humans

Cited by 74 publications

References 31 publications

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation

Sunlight Protection by Vitamin D Compounds

Lichtbedingte Schädigungen: Vorboten von aktinischer Keratose und frühem Plattenepithelkarzinom

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