Enhanced repair of UV-induced DNA damage by 1,25-dihydroxyvitamin D3 in skin is linked to pathways that control cellular energy
Open accessAbstract
Inadequately repaired post-UV DNA damage results in skin cancers. DNA repair requires energy but skin cells have limited capacity to produce energy after UV insult. We examined whether energy supply is important for DNA repair after UV exposure, in the presence of 1α,25-dihydroxyvitamin D 3 (1,25(OH)2 D 3), which reduces UV-induced DNA damage and photocarcinogenesis in a variety of models. After UV exposure of primary human keratinocytes, the addition of 1,25(OH)2 D 3 increased unscheduled DNA synthesis, a measure of DNA repair. Oxidative phosphorylation was depleted in UV-irradiated keratinocytes to undetectable levels within an hour of UV irradiation. Treatment with 1,25(OH)2 D 3 but not vehicle increased glycolysis after UV. 2-Deoxyglucose-dependent inhibition of glycolysis abolished the reduction in cyclobutane pyrimidine dimers by 1,25(OH)2 D 3, whereas inhibition of oxidative phosphorylation had no effect. 1,25(OH)2 D 3 increased autophagy and modulated PINK1/Parkin consistent with enhanced mitophagy. These data confirm that energy availability is limited in keratinocytes after exposure to UV. In the presence of 1,25(OH)2 D 3, glycolysis is enhanced along with energy-conserving processes such as autophagy and mitophagy, resulting in increased repair of cyclobutane pyrimidine dimers and decreased oxidative DNA damage. Increased energy availability in the presence of 1,25(OH)2 D 3 is an important contributor to DNA repair in skin after UV exposure.
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1,25(OH)2D3 is reported to protect against oxidative stress and to modulate DNA damage/repair systems, as well as Nrf2 activation.
“Interestingly, the active form of vitamin D, 1,25(OH)2D3, is reported to protect against oxidative stress [34,35] and to modulate DNA damage/repair systems [[36], [37], [38]], as well as Nrf2 activation [34,39].”
The protective role of the classical active form of vitamin D3 (1,25(OH)2D3) against radiation and UVB-induced damages is recognized.
“the protective role of the classical active form of vitamin D3 (1,25(OH)2D3) against radiation and UVB-induced damages is recognized [36,38,48,49]”
1,25(OH)2D3 has been shown to protect skin against oxidative stress, induce DNA damage/repair process, and activate Nrf2 expression.
“Recently, 1,25(OH)2D3 has been shown to protect the skin against oxidative stress [[34], [35], [36]] and to induce DNA damage/repair process [[36], [37], [38],48] as well as activating Nrf2 expression [34,39].”
These results indicate that in general the vitamin D3 and lumisterol hydroxy-derivatives act like 1,25(OH)2D3 on DNA repair in keratinocytes exposed to UVB.
“These results indicate that in general the vitamin D3 and lumisterol hydroxy-derivatives act like 1,25(OH)2D3 on DNA repair in keratinocytes exposed to the UVB [36].”
CYP11A1-derived hydroxyderivatives of vitamin D3 and lumisterol have the ability to repair UVB-damaged DNA through the DNA repair mechanism described recently for 1,25(OH)2D3.
“Most of the compounds under study enhanced the repair of 6-4PPs in UVB-irradiated cells, suggesting that CYP11A1-derived hydroxyderivatives of vitamin D3 and lumisterol have the ability to repair UVB-damaged DNA through the DNA repair mechanism described recently for 1,25(OH)2D3 [36,38].”
The effects of novel vitamin D3 and lumisterol derivatives, including stimulation of Nrf2-downstream genes and proteins and photoprotection, are similar to those of other synthetic and natural compounds including 1,25(OH)2D3.
“The effects of the novel vitamin D3 and lumisterol derivatives, including the stimulation of the expression of Nrf2-downstream genes and proteins, as well as the photoprotection, are similar to those described for other synthetic and natural compounds including 1,25(OH)2D3 [1,15,17,20,36,50,97].”
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References 86 · Cited by 63
- Authors
- Rybchyn, M. S., De Silva, W. G. M., Sequeira, V. B., McCarthy, B. Y., Dilley, A. V., Dixon, K. M., Halliday, G. M., & Mason, R. S.
- Affiliations
- The University of Sydney (AU)
- UNSW Sydney (AU)
- Corresponding author
- Mason, Rebecca Sara
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 138
- Issue
- 5
- Pages
- 1146-1156
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2771869155
- Cited by
- 63
- References
- 86
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 10 · 2023: 11 · 2022: 8 · 2021: 10 · 2020: 11 · 2019: 5 · 2018: 2 · 2014: 1 · 2013: 1
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council of Australia (APP1070688)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Keywords
- 1,25-dihydroxyvitamin D3, vitamin D, UV-induced DNA damage, DNA repair, keratinocytes, skin cancer prevention, glycolysis, oxidative phosphorylation, cellular energy metabolism, cyclobutane pyrimidine dimers, autophagy, mitophagy, PINK1/Parkin pathway, unscheduled DNA synthesis, photocarcinogenesis
- MeSH terms
- Autophagy, Cells, Cultured, DNA Damage, DNA Repair, Glycolysis, Humans, Skin, Ultraviolet Rays, Vitamin D, Signal Transduction, Keratinocytes, Reactive Oxygen Species, Glycogen Synthase Kinase 3, Membrane Potential, Mitochondrial
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