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Solar UV damage to cellular DNA: from mechanisms to biological effects

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Abstract

Solar ultraviolet (UV) radiation generates bulky photodimers at di-pyrimidine sites that pose stress to cells and organisms by hindering DNA replication and transcription. In addition, solar UV also induces various types of oxidative DNA lesions and single strand DNA breaks. Relieving toxicity and maintenance of genomic integrity are of clinical importance in relation to erythema/edema and diseases such as cancer, neurodegeneration and premature ageing, respectively. Following solar UV radiation, a network of DNA damage response mechanisms triggers a signal transduction cascade to regulate various genome-protection pathways including DNA damage repair, cell cycle control, apoptosis, transcription and chromatin remodeling. The effects of UVC and UVB radiation on cellular DNA are predominantly accounted for by the formation of photodimers at di-pyrimidine sites. These photodimers are mutagenic: UVC, UVB and also UVA radiation induce a broadly similar pattern of transition mutations at di-pyrimidine sites. The mutagenic potency of solar UV is counteracted by efficient repair of photodimers involving global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER); the latter is a specialized repair pathway to remove transcription-blocking photodimers and restore UV-inhibited transcription. On the molecular level these processes are facilitated and regulated by various post-translational modifications of NER factors and the chromatin substrate. Inherited defects in NER are manifested in different diseases including xeroderma pigmentosum (XP), Cockayne syndrome (CS), UV sensitive syndrome (UVsS) and the photosensitive form of trichothiodystrophy (TTD). XP patients are prone to sunlight-induced skin cancer. UVB irradiated XP and CS knockout mouse models unveiled that only TC-NER counteracts erythema/edema, whereas both GG-NER and TC-NER protect against UVB-induced cancer. Additionally, UVA radiation induces mutations characterized by oxidation-linked signature at non-di-pyrimidine sites. The biological relevance of oxidation damage is demonstrated by the cancer susceptibility of UVB-irradiated mice deficient in repair of oxidation damage, i.e., 8-oxoguanine.

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Acknowledgements

This work was supported from grants by Leiden University, Leiden University Medical Center LUMC, Netherlands Organisation for Scientific Research NWO, Dutch Cancer Society KWF, EU and l’Oreal to LM. I thank the postdoctoral and PhD students and staff members who contributed the various studies described in this paper. Particularly I would like to thank Frank de Gruijl (LUMC, the Netherlands) for the longstanding and productive collaboration and introducing me to Jan van der Leun.

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    Leon H. F. Mullenders

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Mullenders, L.H.F. Solar UV damage to cellular DNA: from mechanisms to biological effects. Photochem Photobiol Sci 17, 1842–1852 (2018). https://doi.org/10.1039/c8pp00182k

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