Photorepair of either CPD or 6-4PP DNA lesions in basal keratinocytes attenuates ultraviolet-induced skin effects in nucleotide excision repair deficient mice.
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2022
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Resumo
Ultraviolet (UV) radiation is one of the most genotoxic, universal agents present in the
environment. UVB (280-315 nm) radiation directly damages DNA, producing cyclobutane
pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts (6-4PPs). These
photolesions interfere with essential cellular processes by blocking transcription and
replication polymerases, and may induce skin inflammation, hyperplasia and cell death
eventually contributing to skin aging, effects mediated mainly by keratinocytes.
Additionally, these lesions may also induce mutations and thereby cause skin cancer.
Photolesions are repaired by the Nucleotide Excision Repair (NER) pathway, responsible
for repairing bulky DNA lesions. Both types of photolesions can also be repaired by
distinct (CPD- or 6-4PP-) photolyases, enzymes that specifically repair their respective
photolesion by directly splitting each dimer through a light-dependent process termed
photoreactivation. However, as photolyases are absent in placental mammals, these
organisms depend solely on NER for the repair of DNA UV lesions. However, the individual
contribution of each UV dimer in the skin effects, as well as the role of keratinocytes has
remained elusive. In this study, we show that in NER-deficient mice, the transgenic
expression and photorepair of CPD-photolyase in basal keratinocytes completely
inhibited UVB-induced epidermal thickness and cell proliferation. On the other hand,
photorepair by 6-4PP-photolyase in keratinocytes reduced but did not abrogate these
UV-induced effects. The photolyase mediated removal of either CPDs or 6-4PPs from
basal keratinocytes in the skin also reduced UVB-induced apoptosis, ICAM-1 expression,
and myeloperoxidase activation. These findings indicate that, in NER-deficient rodents, both types of photolesions have causal roles in UVB-induced epidermal cell proliferation,
hyperplasia, cell death and inflammation. Furthermore, these findings also support the
notion that basal keratinocytes, instead of other skin cells, are the major cellular mediators
of these UVB-induced effects.
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Photolesions, Photolyase, Nucleotide excision repair, Xeroderma pigmentosum, UVB ultraviolet radiation
Citação
KAJITANI, G. S. et al. Photorepair of either CPD or 6-4PP DNA lesions in basal keratinocytes attenuates ultraviolet-induced skin effects in nucleotide excision repair deficient mice. Frontiers in Immunology, v. 13, 2022. Disponível em: <https://www.frontiersin.org/articles/10.3389/fimmu.2022.800606/full>. Acesso em: 01 ago. 2023.