Abstract
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.
| Original language | English |
|---|---|
| Article number | 800606 |
| Journal | Frontiers in Immunology |
| Volume | 13 |
| DOIs | |
| Publication status | Published - 29 Mar 2022 |
Bibliographical note
Funding Information:This work was supported by FAPESP (Sao Paulo Research Foundation, SP, Brazil, grants #2019/19435-3 and #2013/08028-1) under the International Collaboration Research from FAPESP and The Netherlands Organization for Scientific Research (NWO, The Netherlands). FAPESP also provided a PhD scholarship and financial support for GSK (#2013/13720-1 and #2015/20368-8). This Project was further supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brasília, DF, Brazil, grant #308868/2018-8), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brasília, DF, Brazil, Financial code 001, grant #88887.337792/2019-00). JHJH acknowledges financial support from the National Institute of Health (NIH)/National Institute of Ageing (NIA) (P01 AG017242; DNA repair, mutations and cell aging), European Research Council Advanced Grant Dam2Age, the European commission EU ITN Address (GA-316390), Dutch research organization ZonMW Memorabel project ID 733050810, ONCODE (Dutch Cancer Society), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project-ID 73111208- SFB 829 as well as European Joint Project on Rare Diseases, RD20-113, acronym TC-NER. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright: Copyright © 2022 Kajitani, Quayle, Garcia, Fotoran, dos Santos, van der Horst, Hoeijmakers and Menck.
