Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewDoes vitamin D protect against DNA damage?
Introduction
Normal cellular metabolism is supported by mechanisms aimed at detecting and repairing DNA damage, with the primary aim of maintaining genome stability. Certain chemicals, including reactive molecules generated during cellular metabolism, can covalently bind to DNA forming mutagenic adducts, which may lead to nucleotide substitution, formation of abasic sites, or formation of single or double strand breaks. Three common threats to the integrity of DNA are: (i) overactivity of spontaneous reactions (mainly hydrolysis) that are intrinsic to the chemical nature of DNA, (ii) endogenous metabolic reactive oxygen or nitrogen species and lipid peroxidation products, and (iii) damage by exogenous physical and chemical agents, e.g. dimerisation of adjacent cytosine or thymine bases by ambient ultraviolet (UV) exposure [1].
Adequate nutrient levels are essential in maintaining genome stability as deficiency can influence toxin absorption, retention, repair and detoxification pathways [2]. One such nutrient is vitamin D, a seco-steroid known for its role in maintaining bone and muscle health [3]. Vitamin D deficiency is associated with increased frequencies of chromosomal aberrations and sister chromatid exchanges due to oxidative, hypoxic and apoptotic stress [4], [5], [6], [7]. Thus maintaining sufficient vitamin D levels is potentially important in preventing these changes.
Vitamin D is mainly produced in the skin through a process initiated by exposure to solar UVB radiation (290–315 nm); pro-vitamin D3 (7-dehydrocholesterol) in the epidermis and dermis is converted, by photolysis, to pre-vitamin D3. Pre-vitamin D3 isomerises rapidly at body temperature to the more thermodynamically stable vitamin D3, (cholecalciferol) [8], [9], [10]. During this transformation process, vitamin D3 moves from the plasma membrane to the extracellular space, and then enters the dermal capillary bed bound to vitamin-D-binding protein [9]. The bound vitamin D3 migrates in the bloodstream to the liver, where it is hydroxylated to 25-hydroxy vitamin D3 (25-(OH)D) (calcidiol), a stable metabolite with a half-life of several weeks [10]. Calcidiol is further metabolised, mainly in kidneys but also in other tissues, to 1α,25-dihydroxyvitamin D (calcitriol), which is the physiologically active form of vitamin D.
Calcitriol is the biologically active form of vitamin D [10], and exerts its effects via two pathways: the classical genomic pathway which involves interaction with vitamin D receptor (VDR) and the rapid response or the non-genomic pathway [11]. The genomic pathway is involved in a host of cellular processes, including some that protect cells against DNA damage, induce cell cycle arrest and, consequently, inhibit cell proliferation, increase apoptosis and induce differentiation [12], [13]. The rapid response pathway is limited to the cis-form of calcitriol [11], [14], and is involved in minimising UV-induced DNA damage by providing in vivo photo-protection [15] (Fig. 1).
Section snippets
Vitamin D and UV induced DNA damage in skin cells.
Exposure of skin cells to UV increases nitric oxide production, thus increasing reactive oxygen species (ROS). These processes are associated with increased oxidative damage, reduced DNA repair, immune suppression and formation of cyclobutane pyrimidine dimers (CPDs) in DNA [16], [17]. CPDs are the most commonly found DNA photo lesions in skin caused by exposure to UV. Calcitriol treatment has been shown to protect skin cells against these hazardous effects of UVB radiation. Pre-treatment of
Vitamin D and DNA oxidation
ROS result in intermediates that can produce peroxides and free radicals. Failure to detoxify these agents can result in oxidative damage and, at the nuclear level, lead to production of abasic sites, purine or pyrimidine oxidation and DNA strand breaks. High levels of oxidative stress in cells, if unresolved, can lead to diseases such as bone loss and cancer. Low serum vitamin D levels have been associated with a reduction in bone density and an elevation in levels of
Vitamin D, micronuclei and DNA strand breaks
Oxidative damage can induce chromosomal aberrations (CA), abnormalities in chromosomal structure that manifest themselves as acentric chromosome fragments and asymmetrical rearrangements such as dicentric chromosomes [30]. These abnormal chromosomes are not segregated properly during mitosis and may result in formation of nuclear anomalies such as micronuclei and abnormal distribution of nuclear material or chromosome loss leading to aneuploidy [31]. Breakage of DNA strands, followed by a
Vitamin D, telomeres and telomerase
Telomeres are DNA hexamer repeat sequences at the end of the chromosomes, and function together with the telosome protein structure to stop chromosome ends from fusing to each other which would cause serious mitotic and genetic aberrations. Telomeres undergo attrition with each cycle of cell replication and may reach a critically short length that no longer enables the telosome structure at the ends of chromosomes to be properly maintained. This, in turn, leads to telomere end fusions and
Vitamin D and DNA damage response
Mammalian cells are equipped with molecular mechanisms to recruit and activate repair at DNA damage sites, through a signal transduction pathway called the DNA damage response (DDR) [46], [47]. This pathway senses DNA damage and sets in place a response to protect genome integrity and overcome the threat by activating and recruiting genome maintenance factors to sites of DNA damage, and coordinating pathways to employ efficient DNA repair. It is mediated by proteins in the
Vitamin D and regulation of the cell cycle
DNA lesions are detected at checkpoints in the cell cycle to block cell proliferation until the DNA is repaired. If irreparable, an elimination process is activated to remove the damaged cell. These processes prevent damaged DNA from being inherited by daughter cells. If unrepaired prior to replication, DNA damage may lead to the propagation of nucleotide substitution or deletion, or chromosome rearrangement [1].
DNA is replicated in the synthesis phase (S-phase) of the cell cycle. In the
Vitamin D and apoptosis
Apoptosis is programmed cell death, a process of cellular self-destruction aimed at maintaining tissue homeostasis or integrity. It is a defence mechanism against the proliferation of genetically aberrant cells within tissues and organs. For example, the degree of metastatic spread of cancer is dependent on the ability of cancer cells to evade apoptosis [48].
Calcitriol has significant antiproliferative effects in vitro and in vivo (reviewed [48]). Apoptosis is mediated by caspase activation,
Vitamin D and DNA damage in humans
Present evidence that vitamin D prevents DNA damage and regulates the cell cycle is limited to results of studies in cultured cells and experimental animal models. While vitamin D may protect against colorectal cancer [82], and perhaps other cancers, in humans, there is currently no direct evidence that this effect, if real, is mediated by way of protection against DNA damage. Importantly, however, in a placebo controlled trial of calcium 2 g/day, vitamin D3 800 IU/day or both for six months, in
Recommendations for dietary vitamin D to prevent DNA damage
There is no substantial evidence at a population level, to directly link vitamin D to prevention of DNA damage. There is some evidence in humans that insufficient to deficient levels of calcidiol are linked prospectively to diseases that have been associated with increased levels of DNA damage [85], [86], [87], [88], [89]. Specifically, insufficient levels of calcidiol (30–50 nmol/L) have been associated with increased risks of diabetes, cardiovascular disease, hypertension, cancer, and multiple
Funding
National Health and Medical Research Council of Australia project grant number 464895.
Conflict of interest
Bruce K. Armstrong has previously held a research grant of $10,000 from Blackmores Ltd., a nutritional products manufacturer that produces vitamin D supplements.
References (92)
- et al.
Vitamin D deficiency promotes growth of MCF-7 human breast cancer in a rodent model of osteosclerotic bone metastasis
Bone
(2010) The cutaneous photosynthesis of previtamin D3: a unique photoendocrine system
J. Invest. Dermatol.
(1981)Vitamin D: its role in cancer prevention and treatment
Prog. Biophys. Mol. Biol.
(2006)- et al.
Vitamin D receptor (VDR)-mediated actions of 1alpha, 25(OH)vitamin D: genomic and non-genomic mechanisms
Best Pract. Res. Clin. Endocrinol. Metab.
(2011) - et al.
The role of vitamin D in cancer prevention and treatment
Endocrinol. Metab. Clin. N. Am.
(2010) - et al.
In vivo relevance for photoprotection by the vitamin D rapid response pathway
J. Steroid Biochem. Mol. Biol.
(2007) - et al.
1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway, J Steroid Biochem
Mol. Biol.
(2004) - et al.
1,25-Dihydroxyvitamin D3 modulates effects of ionizing radiation (IR) on human keratinocytes: in vitro analysis of cell viability/proliferation, DNA-damage and -repair
J. Steroid Biochem. Mol. Biol.
(2010) - et al.
Photoprotection by 1alpha,25-dihydroxyvitamin D and analogs: further studies on mechanisms and implications for UV-damage
J. Steroid Biochem. Mol. Biol.
(2010) - et al.
The nutritional status of astronauts is altered after long-term space flight aboard the International Space Station
J. Nutr.
(2005)
Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress
Food Chem. Toxicol.
The coupling of epidermal growth factor receptor down regulation by 1alpha,25-dihydroxyvitamin D3 to the hormone-induced cell cycle arrest at the G1-S checkpoint in ovarian cancer cells, Mol
Cell Endocrinol.
Anticlastogenic potential of 1alpha,25-dihydroxyvitamin D3 in murine lymphoma
Cancer Lett.
Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin
FEMS Immunol. Med. Microbiol.
Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study
Lancet
Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women
Am. J. Clin. Nutr.
Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D3 through the down-regulation of telomerase
J. Biol. Chem.
A prospective study of telomere length measured by monochrome multiplex quantitative PCR and risk of lung cancer
Lung Cancer
The DNA damage response: making it safe to play with knives
Mol. Cell
1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway
J. Steroid Biochem. Mol. Biol.
A role for the cell cycle phosphatase Cdc25a in vitamin D-dependent inhibition of adult rat vascular smooth muscle cell proliferation
J. Steroid Biochem. Mol. Biol.
Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm
J. Biol. Chem.
Recent developments in cyclin-dependent kinase biochemical and structural studies
Biochim. Biophys. Acta
Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase
Fertil. Steril.
Role of the INK4a locus in tumor suppression and cell mortality
Cell
Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells
J. Biol. Chem.
1 25(OH)2vitamin D3 inhibits cell proliferation by promoting cell cycle arrest without inducing apoptosis and modifies cell morphology of mesenchymal multipotent cells
J. Steroid Biochem. Mol. Biol.
Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis
Neurobiol. Dis.
14th Vitamin D Workshop consensus on vitamin D nutritional guidelines
J. Steroid Biochem. Mol. Biol.
DNA damage, aging, and cancer
N. Engl. J. Med.
The genome health clinic and genome health nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis
Mutagenesis
Optimal use of vitamin D when treating osteoporosis
Curr. Osteoporos. Rep.
Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis
Cancer Res.
Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells
J. Cell Biochem.
Vitamin D deficiency promotes prostate cancer growth in bone
Prostate
Vitamin D: a hormone for all seasons – how much is enough?
Clin. Biochem. Rev.
1alpha, 25-dihydroxyvitamin D3 prevents DNA damage and restores antioxidant enzymes in rat hepatocarcinogenesis induced by diethylnitrosamine and promoted by phenobarbital
World J. Gastroenterol.
Steroid–hormone rapid actions, membrane receptors and a conformational ensemble model
Nat. Rev. Drug Discov.
Inflammatory doses of UV may not be necessary for skin carcinogenesis
Photochem. Photobiol.
An action spectrum for ultraviolet radiation-induced immunosuppression in humans
Br. J. Dermatol.
Topical calcitriol protects from UV-induced genetic damage but suppresses cutaneous immunity in humans
Exp. Dermatol.
1,25-Dihydroxyvitamin D3 and analogues protect primary human keratinocytes against UVB-induced DNA damage
J. Photochem. Photobiol. B
1,25(OH)2 vitamin D3 induces elevated expression of the cell cycle-regulating genes P21 and P27 in squamous carcinoma cell lines of the head and neck
Acta Otolaryngol.
Molecular analysis of p21 promoter activity isolated from squamous carcinoma cell lines of the head and neck under the influence of 1,25(OH)2 vitamin D3 and its analogs
Acta Otolaryngol.
Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial
Cancer Epidemiol. Biomarkers Prev.
Malondialdehyde-DNA adducts in relation to diet and disease risk--a brief overview of recent results
IARC Sci. Publ.
Cited by (67)
Effects of dietary interventions on telomere dynamics
2022, Mutation Research - Genetic Toxicology and Environmental MutagenesisHow far is vitamin D implicated in cutaneous infections
2022, Clinics in DermatologyCometChip analysis of human primary lymphocytes enables quantification of inter-individual differences in the kinetics of repair of oxidative DNA damage
2021, Free Radical Biology and MedicineCitation Excerpt :Key advances described here include the use of the CometChip for analysis of over 1500 samples (equal to over 150,000 comets), which would be exceedingly difficult using the traditional comet assay. Taken together, this work demonstrates the utility of the CometChip for population studies and adds to comet literature pointing to significant differences in DNA repair capacity among individuals [41–58]. Materials.
Vitamin D changes expression of DNA repair genes in the patients with multiple sclerosis
2021, GeneCitation Excerpt :Also, VD did not change the mRNA level of ITPA in MS patients or even in responsive groups. These results are in agreement with other studies indicating that a sufficient VD level is important to prevent DNA damage due to oxidation (Nair-Shalliker et al., 2012) and 8-OHdG reduction (Fedirko et al., 2010). Antioxidants improve cellular defense and the inflammation of demyelination and axonal loss in the animal model of MS (Ferretti et al., 2006).
The relationship between vitamin D and male reproductive and sexual health
2021, Clinica e Investigacion en Ginecologia y Obstetricia