Guide: zinc and
normal DNA synthesis

Chapter 1: The foundations of DNA synthesis

Deoxyribonucleic acid (DNA) is the carrier of genetic information in almost all living organisms. Its duplication — DNA replication — is the precondition for cells to divide and for the body to grow, renew itself and repair.

1.1 The structure of DNA

DNA consists of two strands wound helically around each other, the so-called double helix. Each strand is made up of nucleotides, each consisting of a sugar (deoxyribose), a phosphate group and one of four bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The bases of the two strands are joined to each other by hydrogen bonds — A with T and G with C.

1.2 The steps of replication

1. Initiation: Specific proteins recognise the origins of replication and recruit the helicase that will unwind the double strand.
2. Strand unwinding: The helicase separates the two DNA strands. Single-strand binding proteins (SSBPs) prevent the strands from reassembling.
3. Primer synthesis: The primase lays down short RNA primers that serve as a starting point for DNA polymerase.
4. Elongation: DNA polymerase reads the template strand and adds complementary nucleotides to the new strand. The leading strand is synthesised continuously, the lagging strand in Okazaki fragments.
5. Ligation: DNA ligase joins the Okazaki fragments into a continuous strand.
6. Proofreading: DNA polymerase checks the newly inserted bases and corrects mispairings — a process referred to as proofreading.

1.3 The significance of minerals as cofactors

Several of the enzymes named require metal ions as cofactors in order to develop their catalytic activity. Zinc is one such mineral, for which the EU has authorised a specific health claim in connection with normal DNA synthesis.

Chapter 2: Zinc and normal DNA synthesis

2.1 Biochemical foundations

Zinc (Zn²⁺) is a divalent metal ion that is neither oxidised nor reduced in biological systems. This property makes it a particularly stable cofactor. In the area of DNA synthesis, the involvement of zinc can be demonstrated at several points:

• DNA polymerases: DNA polymerase α, which is involved in the initiation of replication, contains zinc ions. DNA polymerase β too, which takes part in base excision repair, is a zinc-dependent enzyme. The zinc ions stabilise the enzyme structure and enable the correct positioning of the nucleotides in the active site.
• Zinc finger transcription factors: Although transcription factors primarily control gene expression, they also influence the availability of replication factors. Many of these proteins contain zinc finger motifs in which zinc ions determine the three-dimensional folding.
• Tumour suppressor protein p53: The protein p53, often called the “guardian of the genome”, contains zinc in its DNA-binding domain. p53 monitors DNA integrity and, where damage occurs, initiates repair processes or programmed cell death.
• Poly(ADP-ribose) polymerase (PARP): This enzyme recognises DNA strand breaks and recruits repair proteins. PARP-1 contains zinc finger motifs that are necessary for detecting the damaged sites.

2.2 Daily requirement and natural sources

Under EU Regulation 1169/2011 the reference value for daily zinc intake is 10 mg. The following table shows selected foods with their approximate zinc content:

2.3 Bioavailability and absorption

Zinc is absorbed mainly in the jejunum and ileum. The transporter ZIP4 at the apical membrane of the enterocytes takes up zinc ions, while ZnT1 on the basolateral side mediates transport into the bloodstream.

Phytic acid, which occurs in wholegrain products and legumes, can bind zinc and reduce absorption. Soaking, sprouting or fermenting these foods can lower the phytic acid content. At the same time the presence of animal protein can favour zinc uptake, since amino acids such as histidine and cysteine act as ligands and ease transport through the intestinal wall.

Chapter 3: DNA repair — an ongoing process

DNA is constantly exposed to internal and external influences that can lead to damage to the structure. According to estimates, between 10,000 and 100,000 DNA lesions occur daily in every human cell. The body has sophisticated repair systems for fixing this damage.

3.1 Types of DNA damage

• Oxidative damage: Reactive oxygen species (ROS) can modify bases, in particular oxidising guanine to 8-oxoguanine.
• Depurination: The spontaneous loss of a purine base (adenine or guanine) creates an abasic site that has to be repaired.
• Deamination: The spontaneous conversion of cytosine into uracil alters base pairing and has to be corrected.
• Strand breaks: Single-strand and double-strand breaks arise from ionising radiation, certain chemicals or enzymatic processes.

3.2 Zinc-dependent repair mechanisms

Several DNA repair enzymes depend on zinc as a cofactor:

It should be emphasised that the authorised claim refers to normal DNA synthesis — that is, to the physiologically proper course of events given an adequate supply of zinc. No therapeutic or disease-related statement is connected with it.

Chapter 4: Zinc in the cell cycle

DNA synthesis is closely coupled to the cell cycle. In the S phase (synthesis phase) the entire genome is duplicated before the cell moves into mitosis. Zinc is involved at several checkpoints of this cycle.

4.1 Phases of the cell cycle

1. G1 phase: The cell grows and prepares DNA replication. Zinc-dependent transcription factors influence the expression of genes necessary for the transition into S phase.
2. S phase: The actual duplication of the DNA takes place. DNA polymerases with zinc cofactors synthesise the new strand.
3. G2 phase: The cell checks the replicated DNA for errors. Zinc-containing repair enzymes correct any remaining damage.
4. M phase (mitosis): The cell divides into two daughter cells, each of which receives a complete copy of the DNA.

4.2 Control mechanisms and zinc

At the checkpoints of the cell cycle, proteins such as p53 monitor DNA integrity. If damage is detected, the cell cycle can be halted until repair is complete. As already set out, p53 contains zinc as a structural element in its DNA-binding domain.

In addition, cyclins and cyclin-dependent kinases (CDKs) are involved in controlling the cell cycle. The expression of some of these regulators is modulated by zinc finger transcription factors.

Chapter 5: Frequently asked questions

What exactly does the claim “normal DNA synthesis” mean?

The term “normal” in the EU-authorised claim refers to the physiologically proper course of DNA synthesis given an adequate supply of the mineral concerned. It describes no therapeutic effect, no disease prevention and no performance enhancement beyond the normal measure.

How can you assess your own zinc status?

Zinc status is usually determined via the serum zinc level, which can be ordered by a physician. It should be noted that the serum value represents only a snapshot and can be influenced by the time of day, by meals and by inflammatory processes.

Which groups of people have an increased zinc requirement?

The EFSA claims refer to the general adult population. Certain groups — among them pregnant and breastfeeding women, older people and people with chronic intestinal conditions — may have an altered requirement. Individual advice from qualified medical professionals is recommended.

Can you take in too much zinc?

The European Food Safety Authority has set a tolerable upper intake level (UL) of 25 mg per day for adults. Exceeding this limit over longer periods can, among other things, impair copper absorption. Dietary supplements should therefore be dosed according to the manufacturer’s instructions.