Zinc: DNA Synthesis & Cell Division
Molecular Biology
A popular topic in the health sphere has been utilizing saunas and long term fasting to achieve apoptosis and new cell turnover. Using a sauna regularly and occasional long fasts are great practices for a healthy body and metabolism. Exercise is another way to initiate the apoptosis process and start the synthesis of new cells.
I would like to emphasize the importance of taking zinc on this topic. Zinc is required for DNA synthesis and therefore important for building new healthy cells. I want to talk about the particular enzymes and pathways that are involved here.
Why is Zinc Important
About 40% of all the zinc within a cell can be found in the nucleus stabilizing DNA, RNA, and chromosomes as well as a structural component of metalloenzymes within the RNA synthesis pathway and transcription factor proteins.
Metalloenzymes are enzymes which require a metal ion cofactor to function.
Transcription factors are proteins that can bind to DNA sequences and influence the conversion of DNA to RNA by upregulating or downregulating the gene.
Zinc fingers are small proteins that have one or more zinc atoms; they can be incorporated into large proteins for stabilization and can bind to DNA sequences to provide stabilization or recognition for transcription factors. Zinc fingers are very useful and stable molecules that are used all throughout the body; for example, they're needed for new red blood cell synthesis, lipid binding, or even apoptosis regulation. Its estimated that zinc fingers are incorporated or involved with the function of over 1000 transcription factors.
A deficiency in zinc is known to lead to decreased growth, in part by decreasing levels of IGF-1, measured in humans and rats. IGF-1 is a major regulator of the cell cycle, glucose uptake, and amino acid uptake by stimulating a cascade of downstream phosphorylations. The pituitary gland secretes IGF-1 and is known to require the most zinc of any other organ in the body. Interestingly, addition of zinc to diet increased IGF-1 concentrations more than a switch to a high protein diet in mice.1
Besides causing decreased IGF-1 secretion and therefore decreased cell division, zinc deficiency also effects this pathway in another way. Zinc is required to stimulate MAP kinases such as ERK, which translocates to the nucleus and acts as a transcription factor to upregulate genes that lead to cell division. Kinase proteins add phosphate groups to other molecules which can lead to activation or deactivation.
TLDR
Zinc deficiency leads to decreased growth factor secretion, which is needed to tell the cell that it should divide. Growth factors lead to an upregulation of genes that cause increased cell proliferation.
Zinc deficiency also halts the glycogen synthesis pathway. PI3K is a kinase protein which is important for sending the downstream signal in this pathway and depends on proteins that require zinc to function. Zinc is also known to be involved in extracellular signal transduction, second messenger metabolism and the process of phosphorylation in kinase proteins2.
In plain English: zinc is needed to tell your cells what is going on in the rest of the body, and it is needed to help cells act on those signals coming from outside.
For example, Protein Kinase C (PKC) is a metalloenzyme containing 2 or 4 zinc binding sites depending on the isoform. PKC activation is needed for glucose export from the liver when epinephrine is circulating. Zinc is required for its activation and translocation to the nucleus, as well as a structural component to ensure it can bind to the cell's cytoskeleton.
Zinc is also used by proteins and transcription factors that mediate oxidative stress and DNA damage repair; a deficiency is linked to increased levels of oxidative stress. Zinc deficiency leads to an upregulation of tumor suppressor protein p53 in response to increased frequency of single stranded DNA breaks and DNA instability. However, zinc is needed to allow DNA to bind to the p53 protein. Meaning that even though p53 is trying to respond and fix the damage, it can become nonfunctional without enough zinc present3. Zinc deficiency leads to oxidative stress and loss of DNA integrity, opening the door to cancer development or progression4.
Zinc deficiency leads to oxidative stress and an increase in DNA breaks due to DNA instability.
P53 is important for DNA repair and eliminating cancer progression, but it needs adequate zinc to function.
Zinc is involved in the vasodilation and glucagon/epinephrine pathway by affecting the binding of cGMP or cAMP to their corresponding phosphodiesterase (PDE) enzymes. High concentrations of zinc seem to inhibit PDE activity whereas low concentrations activate PDE. While this interaction still needs to be fully elucidated, it is clear that zinc is an important factor in both pathways. PDE enzymes reduce movement through these pathways by de-cyclicating cAMP or cGMP.
PDE enzymes can help slow down a pathway when we no longer need it running full-force; zinc seems to regulate the activity of these enzymes.
The last topic I am going to talk in depth about is RNA Polymerase activity. Zinc is a known requirement for the proper function of these enzymes; the most well studied being RNA pol I and RNA pol II. Zinc deficiency causes degradation of RNA pol II which is in charge of translating mRNA of protein coding genes, and RNA pol I which is in charge of transcribing ribosomal RNA. This is interestingly not seen when there are depletions of other metals like iron or when a cell is starved of amino acids. This leads to the hypothesis that RNA polymerase is degraded to access the stored zinc and redistribute it to enzymes whose activity is completely disabled without it5. These enzymes have an average of 10 zinc atoms within them so their degradation could lead to a significant increase in cellular zinc.
To Wrap Up
There are a ton of other functions of zinc and plenty of pathways I did not cover here including reproduction/fertility, immune system function, wound healing and more. Zinc is essential for proper cell turnover, metabolism, and DNA synthesis and repair. As essential as it is, it can not be stored in the body and needs to be continuously supplied through diet or supplementation. Zinc can be found in red meats, fish, cacao, nuts and seeds such as pumpkin seeds, walnuts, pecans and more.
Symptoms of zinc deficiency include irritability, night blindness, sensitivity to light, eye inflammation, delayed wound healing, lesion formation, inflammation around the nail, weak and brittle nails, nail biting, hair loss and more.
Daily supplementation of 10-15mg per day is recommended for adults, but those with intestinal malabsorption disorders such as IBS may need higher doses upward of 50mg per day. Most people with zinc deficiency notice improvements within 1-3 weeks with daily supplementation6.