Zinc and the gene

doi:10.1016/S0027-5107(01)00067-7

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volume 475, Issues 1–2, 18 April 2001, Pages 161-167

https://doi.org/10.1016/S0027-5107(01)00067-7 Get rights and content

Abstract

A significant portion of cellular zinc is found in the nucleus where it appears to be critically involved in maintaining genetic stability and in the process of gene expression. With regard to gene expression zinc functions mechanistically at several levels but recent interest has focussed especially on the involvement of zinc in DNA transcription through the activity of transcription factors which contain specific zinc-finger regions which bind to DNA and, in conjunction with other families of transcription factors, control cell proliferation, differentiation and cell death. Because of the central importance of zinc in cell division and growth, considerable attention is paid to zinc as an essential trace element and much has been written concerning dietary sources of zinc and recommended dietary intakes of the metal.

Introduction

The potential importance of zinc to the gene can be appreciated from the fact that about 25% of the zinc content of rat liver is found in the nucleus and a significant amount of zinc is incorporated into nuclei in vitro [1]. Mechanistically zinc is involved in the processes of genetic stability and gene expression in a variety of ways including the structure of chromatin, the replication of DNA and transcription of RNA through the activity of transcription factors and RNA and DNA polymerases, as well as playing a role in DNA repair and programmed cell death [2].

The requirement for zinc for growth and cell division is well established and several studies have suggested that DNA synthesis and cell division are more susceptible to lack of zinc than is protein synthesis [3]. Indeed several studies have reported reduced activity of DNA polymerase and thymidine kinase in various tissues following zinc depletion. Further studies have indicated that both DNA and RNA polymerase are zinc metalloenzymes, but this does not seem to apply to thymidine kinase [3]. Loss of DNA polymerase activity does not appear to be reversible by the addition of zinc in vitro which, together with other evidence suggests reduced induction of several enzymes in zinc-deficient tissue [4]. Furthermore, in several models inhibition of thymidine incorporation by zinc deficiency was proportional to the reduction in the number of cells which incorporated thymidine, which suggests that individual cells either incorporate thymidine normally or not at all. In turn this is indicative of a role for zinc in the induction of enzymes needed for DNA synthesis in the S phase of the cell cycle [5].

In several studies with mammalian cells in vitro in which zinc deficiency was induced by addition of EDTA to the culture medium, the reduction in DNA synthesis was greater than that of RNA or protein, and required the EDTA to be present for some time before DNA synthesis was affected. All effects of EDTA were reversible specifically by added zinc, which again points to an involvement of zinc in metabolic events preceding DNA synthesis rather than DNA synthesis per se [3].

Section snippets

Zinc-finger proteins

Recently, increasing emphasis has been placed on the role played by zinc in zinc-finger proteins, which are mainly nuclear transcription factors which, together with other families of transcription factors (i.e. homeobox, leucine zipper and helix loop), control cell proliferation, differentiation and apoptosis through regulation of gene expression [5]. In the zinc-finger proteins the zinc-fingers, or DNA-binding motifs, are arranged in different combinations and can recognise a large range of

DNA replication

With respect to the DNA replication an important zinc-finger protein is the mammalian single-strand DNA binding protein known as replication protein A (RPA) which is essential for DNA replication and repair. RPA consists of three subunits the largest of which contains a zinc-finger motif that lies outside of the domain required for binding to single-strand DNA or for forming the RPA holocomplex, but which is required for optimal DNA binding activity [8], [9]. RPA is essential for DNA

DNA repair

DNA repair mechanisms are highly complex and varied but two major systems appear to be operative in eukaryote cells.

•
Base excision repair (BER), with a highly specific recognition mechanism and in which the DNA glycosylase, which recognises and binds to the damaged DNA base, is catalytically active and cleaves the glycosidic bond between the damaged nucleotide and the deoxyribose backbone. In doing so these glycosylases generate apurinic/apyrimidinic (AP) abasic sites. Subsequently, an AP

Apoptosis

Apoptosis or programmed cell death is a major form of cell death, which is characterised by a series of morphological changes involving condensation of nuclear material and vacuolisation of the cytoplasm.

The precise mechanisms underlying the triggering of apoptosis are not clear but damage to DNA and activation of the p53 gene appears to be an important component of the process as also is activation of certain members of the caspase family of proteases. Zinc is involved to some extent in both

Metallothionein

Metallothionein (MT) are proteins consisting of a single polypeptide chain of 61–62 amino acids containing 20 cystein residues which contain several bivalent cations (zinc, copper, cadmium, mercury) bound through metal-thiolate linkages. Physiologically induction of MT appears to be principally involved in detoxification of heavy metals and metabolism of several essential trace elements. However, induction of MT by other stimuli including X-, γ- and UV-irradiation and several anticancer

Antioxidant protection of DNA by zinc

In general, oxidative damage to DNA appears to be due primarily to OH radical dot . However, this reactive species is so short-lived that, except for ionising radiation or other systems which release OH in close proximity to DNA, most nuclear OH probably arise from reactive species such as O₂ or H₂O₂ which diffuse into the nucleus and undergo Fenton-type reactions with DNA bound ferrous iron to release OH radical dot [29]. In this context an important role has been recognised for less redox active zinc in displacing

Dietary zinc intakes, recommended dietary intakes and DNA damage

Severe zinc deficiency in humans is rare but mild deficiency has been reported occasionally in sections of free-living populations, especially at early stages of the life cycle (i.e. infancy and childhood) when zinc requirements are relatively high [51]. The clinical features of mild zinc deficiency are not obvious but may include a reduced growth rate and impaired resistance to infection [52]. The central role played by zinc in DNA synthesis and cell proliferation may well contribute

Future research needs

Because of the wide range of circumstances in which zinc interacts with DNA stability and metabolism, it is not possible to define a precise area of greatest research need. Clear evidence exists from many animal studies and some human surveys that a very early effect of zinc deficiency is manifest in growth retardation. The extent to which this impairment arises from the extensive involvement of zinc in DNA metabolism is not clear, but it is highly likely to contribute to growth retardation in

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Citation Excerpt :
Zinc (Zn) is a trace mineral involved in several cellular processes, such as proliferation, immune function, antioxidant defense, gene expression, and ARN polymerase activity [1–3].
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View full text

ReviewZinc and the gene

Abstract

Introduction

Section snippets

Zinc-finger proteins

DNA replication

DNA repair

Apoptosis

Metallothionein

Antioxidant protection of DNA by zinc

Dietary zinc intakes, recommended dietary intakes and DNA damage

Future research needs

Trends Biol. Sci.

J. Inorg. Biochem.

Biochimie

Trends Pharmacol. Sci.

Exp. Cell Res.

Mutat. Res.

Chemico-Biol. Interactions

Toxicol. Appl. Pharmacol.

Toxicol. Lett.

J. Biol. Chem.

A role for zinc in the regulation of gene expression

Proc. Nutr. Soc.

The molecular basis for the role of zinc in developmental biology

Mol. Cell. Biochem.

Possible site of Zn control of hepatoma cell division in Wistar rats

J. Natl. Cancer. Inst.

Exploring the role of the homeobox and zinc finger proteins in pancreatic cell proliferation, differentiation and apoptosis

Int. J. Pancreatol.

Zinc fingers in Caenorhabditis elegans: finding families and probing pathways

Science

Replication protein A (RPA): the eukaryote SSB

Crit. Rev. Biochem. Mol. Biol.

The DNA damage recognition problem in human and other eukaryote cells: the XPA damage binding protein

Biochem. J.

Review
Zinc and the gene