The effects of zinc on DNA integrity may not be limited to zinc's anti-oxidant properties. Zinc plays a critical role in the regulation of transcription and replication of DNA through zinc finger proteins. Additionally, many DNA repair mechanisms involve zinc. Many proteins involved in both base-excision repair and nucleotide-excision repair are zinc finger or zinc-associated proteins. For example, the tumor suppressor protein p53 plays an important role in coordinating events leading to appropriate DNA repair. The p53 protein plays a role in modulating cell cycle progression, apoptosis, DNA repair and cell proliferation/differentiation.114 Also, p53 is most well known for its ability to induce G1 arrest in the cell cycle, allowing the cell to induce adequate repair of DNA before cellular division.115 Notably, the prevalence of p53 mutations in tumors is very high. In fact, over 50% of human malignancies contain a mutation in p53.116 The majority of these mutations are found in the region of the gene that encodes for the DNA-binding region of p53.117,118 This binding region also contains the zinc-binding domain. Several lines of evidence suggest that p53 acts, in part, as a DNA-binding protein.119 Thus, to coordinate the events related to DNA repair, p53 must be able to bind to specific DNA-binding domains to transcriptionally activate downstream targets involved in DNA repair. An increase in p53 protein expression with zinc deficiency was found in several different cell lines.120,121 An upregulation in p53 expression is seen both in chemically induced zinc deficiency (using an intracellular zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine TPEN) and by feeding cells zinc-deficient media. This upregulation of p53 expression is most likely in response to DNA damage induced by zinc deficiency. Although there is an increase in p53 expression with zinc deficiency, there is evidence that p53 may be dysfunctional and, hence, DNA repair would be severely compromised. A marked decrease in the ability of p53 to bind to downstream DNA targets has been found with zinc deficiency.105 Because the p53 protein is a transcription factor, the ability of p53 to bind to DNA promoter regions is critical for coordinating the events that control DNA repair and apoptosis. Thus, despite increases in p53 protein level in zinc-deficient cells, this p53 is likely dysfunctional, and activation of gene transcription of specific genes needed for DNA repair could be compromised.
The DNA-binding activity of p53 is largely mediated by a conformation-sensitive structure in the central portion of the protein (residues 102-292).118 Mutations in this region cause an 'unfolding' of this structure and a loss of binding activity. Other researchers have also found that the removal of zinc, by either chemical chelation or adding zinc-deficient media, alters the expression of p53.122,123 Direct chemical chelation also appears to reversibly alter p53 conformation, with the loss of DNA-binding activity.124 Thus, zinc deficiency may render the p53 protein to adopt a 'mutant-like' conformation that will alter the cell's ability to appropriately respond to DNA damage.
The effect of zinc deficiency was also investigated on the expression of apyrimidic endonuclease (APE), an important endonuclease in base-excision repair.125 DNA base-excision repair is a major pathway responsible for the repair of both cellular alkylation and oxidative DNA damage. A critical step in this pathway involves the cleavage of damaged sites in DNA by APE. APE (which is also known as Ref. 1) is a multifunctional protein that not only repairs AP sites, but also controls DNA-binding activity, via redox mechanisms, of numerous transcription factors that are involved in cancer promotion and progression (such as AP-1, NFkB, p53).126 In addition, APE levels appear to be elevated in a number of cancers.127 129 Zinc deficiency increases the expression of APE, most likely in response to DNA damage induced by zinc deficiency.105 These transcription factors play important roles in controlling oxidative stress responses and cell proliferation.130,131 Perturbations in their binding and signal pathways could significantly impair the cell's ability to handle oxidative stress and ultimately be very detrimental to the cell. We have also found a marked decrease in binding of AP1 and NFkB with zinc deficiency. 105 Other investigators have also detected alterations in NFkB signaling with zinc deficiency.132 Therefore, the impact of zinc status on DNA integrity is most likely a multi-layered process involving both increases in oxidative stress and combined perturbations in DNA repair and other oxidant-sensitive signal pathways.
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