The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis

Cell Death and Differentiation
Marius PolletThomas Haarmann-Stemmann

Abstract

Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR-/- mice, and critical for the improvement of NER. Besides increasing NER activity, AHR inhibition was accompanied by an enhanced occurrence of DNA double-strand breaks triggering KC apoptosis at later time points after irradiation. The UVB-activated AHR thus acts as a negative regulator of both early defense systems against carcinogenesis, NER and apoptosis, implying that it exhibits tumo...Continue Reading

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Citations

Sep 26, 2019·Frontiers in Medicine·Takanori HidakaSetsuya Aiba
Aug 14, 2020·International Journal of Cancer. Journal International Du Cancer·Miriam MengoniThomas Tüting
Jun 20, 2019·Nature Reviews. Immunology·Jamie J BernardJean Krutmann
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Dec 5, 2019·International Journal of Molecular Sciences·Christian VogeleyThomas Haarmann-Stemmann
Dec 19, 2019·Frontiers in Plant Science·Paula LlabataMarie-Theres Hauser
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Jan 2, 2021·The Journal of Investigative Dermatology·Mariela KyorevaPaola Di Meglio
Jan 28, 2021·International Journal of Molecular Sciences·Monika SzelestTomasz Plech
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Jan 6, 2021·International Journal of Molecular Sciences·Zhongyan WangDavid H Sherr
Dec 17, 2021·Acta Pharmacologica Sinica·Wei-Wei LiuTakashi Ikejima

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Methods Mentioned

BETA
biopsies
irradiated
FACS
co-immunoprecipitation
transgenic
PCR
transfection
Assay
electrophoresis
genotyping

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