Zinc (Zn) is an essential micronutrient for human health and the role of Zn in maintaining genomic stability and function is undeniably crucial. The role of Zn in for gene function is important as Zn is involved in various processes including gene expression, DNA repair, apoptosis as well as DNA replication and RNA transcription through Zn finger proteins. Given the fact that Zn is a required cofactor for antioxidant defence proteins and DNA repair enzymes, it is important to determine the effect of Zn on genome stability which increases the risk of cancer and other diseases. This review will focus the role of Zn in maintaining DNA integrity and deficiency can contribute to genomic instability.
1.1 Genomic stability and cancer: How nutrition is vital?
More than 10 million new cases of cancer worldwide including 7 million cancer deaths were reported in 2002. In 2020, new cases are estimated to rise to over 16 million with a mortality rate of at 10 million cases . The links between diet and cancer have been under investigation since the 1980s. Although unravelling the links between diet and cancer is complex, the need for research in this area is important as dietary constituents may modify a multitude of processes in both normal and cancer cells and eventually influence susceptibility risk [2,3].
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The fact that nutrition can affect fundamental cellular processes could impact on the development of cancer cells. Figure 1 illustrates how nutrition and/or diet can contribute to cancer development. In order to unravel the association between diet and cancer, the biological process underpinning the cancer processes need to be better understood.
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Figure 1: Food and nutrition can affect fundamental biological processes which can promote or inhibit the development of cancer (modified from )
The involvement of genomic stability in the development of cancer is well known . Cancer is a disease of altered gene expression and/or DNA mutation. Therefore, one of the key components in cancer intervention studies is the maintenance of genomic stability. Recent research has focussed on the involvement of micronutrients in determining genomic stability events as deficiency can affect all the relevant pathways, namely DNA repair, DNA synthesis and apoptosis [4,5]. Figure 2 illustrates the effect of micronutrients in maintaining DNA integrity. It has been shown that micronutrient deficiency can produce DNA damage resulting in increased cancer risk, higher incidence of infertility and accelerated ageing [5,6].
Figure 2: Main concept of gene-diet interaction as micronutrient deficiency has the same impact as exposure to genotoxins which affect genomic stability, fertility and the ageing process (adapted from )
Dietary deficiency in key micronutrients required for DNA maintenance may produce similar effects as inherited genetic disorders  and may damage DNA to an extent similar as significant exposure to known carcinogens such as ionising radiation . A number of laboratory and epidemiological studies suggest that low intake of minerals could be a major risk factor for several types of cancers [8,9]. Besides, evidence shows that dietary deficiencies in minerals can result in DNA-strand breaks and oxidative lesions that are similar to radiation induced DNA damage [10,11].
The need to understand the role of micronutrients and genomic stability is important in order to provide a better strategy for cancer prevention by exploiting potential gene-micronutrient interactions. Therefore, one of the aims of this review is to provide a better understanding for the role of one of the more important micronutrients, namely zinc in maintaining genomic stability.
1.2 Zinc Functions
Zn (Zn) is an important micronutrient to maintain DNA integrity. Zn can be found ubiquitously in the environment and possesses a number of biological functions, ranging from cell proliferation to hormonal activities . Zn is essential in maintaining human health and a large body of evidence shows the important role of this metal in maintaining DNA integrity. The function of Zn involve a wide range of biological processes including cell proliferation, reproduction, immune function and defence against free radicals [12-17]. In addition, Zn appears to regulate key physiological processes such as response to oxidative stress, DNA repair, cell cycle and apoptosis . It is known that more than 100 specific enzymes require Zn for their catalytic functions . Thus, Zn appears to have a critical role in cellular processes and genomic stability.
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Zn also has a significant impact on DNA as a component of chromatin structure, DNA replication, transcription and DNA repair .In addition, Zn is one of the components for more than 1000 proteins including copper/Zn superoxide dismutase and Zn finger proteins . The role of this metal in copper/Zn superoxide dismutase shows that Zn plays an important role in cellular defence mechanisms that aim to preserve the cell against oxidative stress.
Previous evidence shows genomic instability as one of the main reasons for increasing cancer risk [7,8,19-22]. The fact that Zn is required as a cofactor in DNA metabolism, suggested that deficiency in this micronutrient may induce important chromosomal mutations that increase cancer risk. Dreosti (2001) has shown that Zn deficiency will cause increased DNA oxidation, DNA breaks and elevated chromosome damage rate .
1.3 Sources of Zn and Zn deficiency
Major sources of dietary Zn include red meat, eggs, nuts and whole grains . Whole grains and legumes also contain Zn but the Zn in these sources may be much less bioavailable due to high phytate concentration which leads to the hypothesis that vegetarians and vegans may be at increased risk for Zn deficiencies .
Zn deficiency can occur in populations with low dietary Zn intake and high concentrations of phytate. Phytate or myo-inositol hexaphosphate, better known as phytic acid consists of six phosphate ester groups . Phytate is a powerful divalent metal chelator and is mainly found in nuts, seeds and grains. The role of phytate as a strong chelator for metals including Zn contributes to being deficient for this mineral . In addition, Zn absorption was also found to be inhibited by the presence of calcium, although it may only happen when phytate is also present in the diet . Formation of insoluble complexes of calcium-Zn-phytate may cause this inhibitory effect. Coffee and milk have been shown to reduce bioavailability of Zn in human subjects .
In contrast, higher protein content was found to increase Zn absorption. Although casein was found to inhibit Zn absorption, animal protein derived from read meat and eggs inclusive of whey protein was reported to enhance the effects of Zn absorption .
Based on individual requirements for Zn and the absorbable content of each nation's food supply, it has been estimated that approximately 20.5% of the world's population are at increased risk of inadequate Zn intake . Populations that are at high risk of Zn deficient include individuals at early stages of the life-cycle (ie. infants and childhood) when requirements of Zn are high. In addition, patients with gastrointestinal disorders such as malabsorption syndrome, diverticulitis, active Crohn's disease and liver cirrhosis are predisposed to a reduction of Zn absorption [27-29]. The elderly have an increased risk of Zn depletion because Zn absorption may be impaired with increasing age and they tend to consume low-Zn diets . Mild Zn deficiencies are highly prevalent in developing countries and severe Zn deficiency are commonly found in third world countries as they tend to have a low Zn content within their daily meal .
The link between Zn and cancer has been established in both in vivo and in vitro studies. Zn status is compromised in cancer patients compared with healthy controls [31-34]. In rats, dietary Zn deficiency causes an increased susceptibility to tumor development when exposed to carcinogenic compounds . Insufficient intake of Zn also may contribute to oesophageal cancer in both humans [36,37] and rats . Zn deficiency can also been shown to lead to testicular cell DNA damage [39-42] and impairs cognitive function in both experimental animals and humans [43-48].
These results showed that zinc deficiency may have a significant impact in increasing cancer risk. It may be due to the fact that zinc plays a key role in DNA repair, DNA integrity and DNA transcription and replication. The next question that will be asked is how Zn can affect DNA damage. This will be discussed in the next topic.
Zn deficiency and DNA Damage
Previous studies have shown that Zn depleted cells may impair DNA repair mechanism and hence induced an elevated DNA damage rate [17,18]. In 2003, the same group found that Zn deficiency induced oxidative DNA damage and p53 expression in human lung fibroblast . They found that Zn depleted cells caused downregulation of some DNA repair genes indicative for compromised DNA repair mechanism. In addition, they also found that Zn deficiency downregulates several protein involved in both stress response and protein degradation and these indirectly affect transcription of DNA damage and repair genes. p53 gene is increased and these leads to conclusion where Zn deficiency provides and environment for increased oxidized DNA damage with a decreased abitility to repair this damage .
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In recent research, Zn deficiency was found to alter DNA damage response genes in normal human prostate epithelial cells [50. In the study, it was shown that low cellular Zn levels caused DNA damage and altered expression of cell cycle genes, apoptosis, DNA damage, repair and transcription. This study confirms an important role for Zn in maintaining DNA integrity and how Zn depletion may impair cellular mechanisms that could result in accumulation of DNA mutations leading to increased cancer risk.
Increase p53 - Zn deficiency provides an environment for increased oxidized DNA damage with a decreased ability to repair this damage (Ho et al 2003)
Upregulation of certain DNA damage and repair genes (Ho et al 2003)
Down regulation of some DNA repair genes - DNA repair mechanism may be compromised (Ho et al 2003)
Downregulation of several protein involved in both stress response and protein degradation - indirectly affect transcription of DNA damage and repair genes (Ho et al 2003) = Zn deficiency induced oxidative DNA damage and p53 expression in human lung fibroblast
Zn deficiency affects DNA damage, oxidative stress, antioxidant defense and DNA repair in rats (Song et al 2009)
Severe Zn depletion caused an increase in DNA damage in peripheral blood cells than in control group (Zn adequate) - impairments in DNA repair - compromised p53, DNA binding and differential activation of the base excision repair proteins 8-oxoguanine glycosilase and polyADP ribose polymerase (Song et al 2009)
Both severe and marginal Zn deficiency in vivo increases oxidative stress, impairs DNA integrity, increase DNA damage in rat peripheral blood cells
Marginal Zn deficiency increases oxidative DNA damage in the prostate after chronic exercise (Song et al 2009)
MZD increased p53 and PARP expression but no change in 8-hydroxy-2'-deoxyguanosine levels was detected (Plasma Zn - 2.54 Â± 0.22 Âµg/ml) compared to MZA (3.19 Â± 0.22 Âµg/ml)
Tail moment of peripheral blood cells in MZD group - 20% higher than in the ZA group
Prostate 8-OHDG - MZD - 32% higher than ZA group
8 OHDG concentration significantly correlated with the tail moments of peripheral blood cells
Dietary Zn depletion (6 wk) is associated with DNA strand breaks in peripheral blood cells (day 13 compared with day 55; p<0.05), changes were ameliorated by Zn repletion (day 55 compared to day 83; p<0.05) (Song et al 2009)
Plasma Zn concentrations were negatively correlated with DNA strand breaks (r=-0.60, p=0.006) during the Zn-depletion period (Song et al 2009)
Increase in single strand DNA breaks were observed in PrEC grown in ZD media compared with cells grown in Zn-adequate media for 7 d (p<0.05) (Yan et al 2008)
Differential expression of genes involved in DNA damage response and repair, tumor protein p73, MRE11 meiotic recombinant 11 homolog A, tp53 ; western blot - increased p53 experssion with ZD
ZnSO4 - induce time and dose dependent cytotoxicity - resulting in oxidative stress, suppression of antioxidant system & activation of p53-dependent apoptosis - Zn supplementation (100 ÂµM) markedly reduced DNA damage at all treatment times ; Zn depleted cultures showed massive DNA damage at 6h of treatment (Rudolf & Cervinko 2006)
Zn supplementation and DNA damage
Zn chromate - induces chromosomal instability and DNA double strand breaks in human lung cells , MRE11 expression increased, ATM and ATR - phosphorylated - indicating that DNA double strand breaks repair system initiated (Xie et al 2009)
Zn citrate compound (CIZAR) 1 mM- cytotoxic against choriocarcinoma cell lines (Bae 2007) - apoptotic inducer
Zn oxide nanoparticles - reduction in cell viability, increased DNA strand breaks - human epidermal cell lines
Figure X: Schematic diagram proposed for effects of Zn deficiency on genome stability and DNA integrity This event will block critical signals within the DNA repair pathway. Abbr : ZnDF - Zn Deficiency, AP1 - activator protein 1, NFÄ¸B - nuclear factor kappa-light-chain-enhancer of activated B cells, APE/Ref-1 - apyrimidinic endonuclease/redox factor-1, p53 - p53 tumor suppressor genes.
Although Zn appears to have multiple functions in cellular processes, it may also have the potential to induce adverse effects.
High concentrations of Zn in drinks, up to 2500 mg/L have been associated with poisoning of individuals, causing nausea, abdominal cramping, vomiting, tenesmus and diarrhoea with or without bleeding [51.
Limited numbers of studies have been undertaken in order to understand the effect of Zn excess to cellular functions.
Data by WHO (2001) suggested excess of Zn during embryogenesis can be teratogenic or lethal. However, Zn appears not to be classified as either a mutagen or carcinogen [51,52.
Biochemical analysis has shown that Zn can inhibit the activity of some DNA repair proteins,including N-methylpurine-DNA glycosylase and DNA ligase 1 [Wang et al., 2006].
At sublethal doses, Zn supplementation in cultured cells may suppress tumorigenesis by induction of DNA damage responses, including a G2/M checkpoint response in the precancerous human bronchial epithelial cells [Wong et al., 2008].
There is no evidence of adverse effects from naturally occurring Zn in food.
Current evidences on Zn and genomic stability
Zn and Genome Stability
MN - originate from chromosomal fragments/whole chromosome that lag behind at anaphase during nuclear division
MN - small, extranuclear bodies that arise in dividing cells from acentric chromosome/chromatid fragments
Misrepair of two chromosome breaks may lead to an asymmetrical chromosome rearrangement - resulted in dicentric chromosome and an acentric fragments
Centromeres of the dicentric chromosomes are pulled to opposite poles of the cells at anaphase resulting in the formation of a NPB between the daughter nuclei and an acentric fragment that lags behind to form a MN
MN harbouring whole chromosomes are primarily formed from defects in the chromosome segregation machinery - failure of mitotic spindle; failure of kinetechore/other parts of the mitotic apparatus; damage to chromosomal substructures, mechanical disruptions; hypomethylation of centromic DNA
MN arise by gene amplification via breakage-fusion-bridge cycles when amplified DNA is selectively localized to specific sites at the periphery of the nucleus & eliminated via nuclear budding
Micronuclei as predictor of nutritional deficiency
comprehensive CBMN assay - assessing the effects of micronutrients on genome stability and cell death
An increase in the level of MN, NPB and NBuds with a decrease in the folic acid concentration from 120 - 12 nmol/l, coincides with the physiological range in the serum of individuals consuming unsupplemented diet (8-35 nmlm/l) (ref)
Cross sectional studies performed on lymphocytes of vegetarians and non vegetarians, older men and young adults indicated that MN frequency was negatively correlated with plasma folate & B12, positively correlated with homocysteine and vit C & unrelated to vit E status (REF)
Depletion-repletion study in nine-post menopausal women and placebo - controlled dietary in nine post menopausal women and placebo - controlled dietary intervention studies have demonstrated that supplementation with specific micronutrients can lead to a reduction in Mn frequency
Optimal level of micronutrient intake that can minimize genome damage
Optimal micronutrient concentration may exceed normal intake levels from diet
Sensitivity of the MNi index to small variations in micronutrient status within the physiological range - excellent biomarker for identifying dietary factors that are essential for genome stability and for defining their optimal intake levels
Future use for Zn status as plasma Zn - controversial - not a very sensitive biomarker
MN and Zn
there are only 5 studies that used CBMN assay to observe genome stability effect of Zn
Induction of MN in Zn chloride treated human leukocytes - significant increase of micronucleated cytokinesis blocked cells compared to negative control - not in dose dependent manner (Santra 2002) - concentration used 15 mM and 30 mM
supplementation with polypill - Î²-carotene (18 mg), vitamin C (900 mg), vitamin E (d-Î±-tocopherol succinate-250mg), Zn (12 mg) - reduced the Mn index by 13% - 6 months trial (Fenech et al 2005)
MT plays a protective role against low dose of X-Ray injury - pretreatment with Zn sulphate at 100 Âµmol/kg suppressed bone marrow injury caused by low dose of X-irradiation in the wild type mice but not in MT1/MTII null mice-measured via increase of reticulocytes with micronuclei & polychromatic erythrocytes with micronuclei in MT1/MTII null mice
Induced MN in Algerian mice treated with Zn acetate- measured by MN polychromatic erythrocytes - bone marrow - 5/10 doses of 1.5 mg/kg BW - minimal frequency compared to lead and Cd (Torres-Tapisso et al 2009)
Zn dimethyl and Zn diisonyldithiocarbamate did not induce MN in human lymphocyte cultre (Zenzen et al 2001)
No human study that look into effect of Zn supplementation against Mn index - remain unexplored
No study on Zn using CBMN-Cyt assay in vitro - we are the first to demonstrate that low Zn may increase genome instability with significant increase in micronuclei, NPB and NBuds frequency
Zn and Methylation
Methylation of cytosine in CpG sequence plays an important role in the suppression of expression of parasitic DNA and housekeeping genes
Cancer and ageing - global DNA methylation is reduced; methylation of specific CpG island is increased - could lead to unwanted silencing of housekeeping or tumour suppressor genes
Prevention of genomic instability - prevention of integration of oncogenic virus DNA
Prevention of hypomethylation - enable a better surveillance of foreign DNA integration into human DNA
Global methylation - suggested to lead to neoplastic transformation through the induction of genomic stability
Zn deficiency - reduce the utilization of methyl groups from SAM in rat liver, resulting in genomic DNA hypomethylation and histone hypomethylation (wallwork & Duerre 1985; Dreosti 2001)
Betaine-homocysteine-S-methyltranferase (BMHT) is a Zn metalloenzyme that catalyses the transfer of methyl group from betaine to homocysteine to produce dimethylglicine (DMG) and methionine (Breksa & Garrow 2005)
DNA methylation - addition of a methyl group to deoxycytosine to form deoxymethylcytosine within a CG nucleotide (CpG site) (Richardson 2003)
CpG sites may be clustered in regions of higher frequency termed CpG island, which are defined as regions of DNA > 200 bp in length with >50% content being C & G residues (Gerdiner-garden & Frommer 1987)
DNA methylation is mediated by the DNA methyltransferase (DNMT) enzymen family, which includes DNMT1, 3a, 3b
DNMT1 - responsible for the maintainance of DNA methylation patters and has a preference for hemi-methylated DNA
DNMT 3a & 3b - associated with de novo methylation of previously unmethylated cpG sites (Bestor 1988; Okano 1998)
Progression of ageing and development of cancer are associated with aberrant DNA methylation patterns, typically global hypomethylation & gene specific hypermethylation (Richardson 2003)
Specific dietary components are known to affect mammalian DNA methylation status (mathers & Ford 2009) - affecting the supply of methyl groups as substrates for DNA methylation reaction or through affecting the activity of specific DNMT (Niculescu & Zeisel 2002)
Methionine cycle - key in the production of universal methyl donor S-adenosylmethionine, sensitive to a number of micronutrient deficiencies including Zn (Maret & sandstead 2008)
Depletion in DNA methylation following exposure to Zn deficient diet may be the result of a reduction in the function of Zn-dependent enzyme in the methionine cycle - such as betaine-homocysteine methyltransferase (Maret and sandstead 2008; evans et al 2002)
Zn and Telomeres
What is telomere? -
How Zn can affect telomere
Zn and Human Tankyrase1 - Zn binding catalytic domain in TANK1 (Lehtio et al 2008) - TANK1 - PARP family
Liu et al 2004 - Zn Sulphate - 80 ÂµM - accelerated telomere loss in Hepatocytes L-02 and Hepatoma cells SMMC-7721 - 4 weeks
Telomere end fusion and BFB cycle
Cells with short telomeres is associated with impaired Zn homeostasis - Cipriano et al 2009
Fig. X : Adapted from Thomas & Fenech 2007 - BFB cycle resulting from telomere end fusions. (A) Chromosomes with shortened telomeres form a dicentric chromosome resulting from telomere end fusion. (B) The dicentric chromosome is replicated during S phase (C) and centromeres are pulled at opposite ends of the poles at anaphase (D). Uneven breakage of the dicentric chromosome results in altered gene dosage producing daughter cells containing extra gene copies (amplification) (F) whilst the remaining daughter cell (E) has a deleted gene copy number. The multiple copy number chromosomes may fuse again to form a dicentric chromosome housing increased gene copy number (G). The dicentric is further replicated at (C) and the cycle is repeated.
RDA for genome stability
Redefine RDAs for the prevention of degenerative disease - caused by DNA damage
In vitro experiments indicate that DNA breaks in cells are minimized when Zn concentration in culture medium is at 4 ÂµM (Ho et al 2002/in vitro experiments - Ho's group)
Put table that showed zn concentration which can optimize DNA integrity/ (in vivo study) - plasma Zn (optimized DNA strand breaks) (Table 1)
In vitro may not predict in vivo requirements - we can't extrapolate the data to human population because of numerous metabolic system in the body - provide useful guide of optimal concentration range for genome health
RDA for Zn - 14 mg/day for men and 8 mg/day for women (Nutrient reference Values Australia and New Zealand)
Dietary intakes above the current RDA may be particularly important in those with extreme defects in the absorption and metabolism of the micronutrients - ageing is a contributing factor
Prevention of diseases caused by genome damage is to take into consideration the genotype of individuals - common genetic polymorphism - impact on bioavailability of micronutrients
IL6 polymorphism - affects MT - less potent antioxidant - higher DNA damage - prone to various diseases = interactions between the polymorphism leads to genome instability