Messenger RNA (mRNA) synthesis using DNA as the template is called transcription. The mRNA carries genetic information from the DNA of the chromosomes in the nucleus to the surface of the ribosomes in the cytosol. It is synthesized as a single strand. Chemically, RNA is similar to DNA. It is an unbranched linear polymer in which the monomeric subunits are the ribonucleoside 5' monophosphates. The bases are the purines (adenine and guanine) and the pyrimidines (uracil and cytosine). Thymine is not used in mRNA. Instead, uracil is used. This base is not present in DNA. Messenger RNA is much smaller than DNA and is far less stable. It has a very short half-life (from seconds to minutes or hours) compared to that of nuclear DNA (years). Because it has a short half-life, the purine and pyrimidine bases that are used to make mRNA must be continually resynthesized. This requires the same array of nutrients noted previously for DNA synthesis.
The synthesis of mRNA from DNA occurs in several stages: initiation, elongation, editing (processing), and termination. Initiation of transcription (the synthesis of mRNA) occurs when factors that serve to stabilize nuclear DNA are perturbed. Perturbation signals pass in to the nucleus and stimulate transcription. A small portion of the DNA (^17,000 bases) is exposed and used as the template for mRNA synthesis. The exposed portion also contains one or more sequences that have control properties with respect to the initiation of transcription. This region is called the promoter region and represents a key site for nutrient interaction. The promoter region precedes the start site of the structural gene and is said to be upstream of the structural gene. Those bases following the start site are downstream. The exposed DNA contains groups of bases called exons and introns. The introns are noncoding and are removed by editing prior to the movement of the mRNA from the nucleus to the cytosol.
Transcription is highly regulated. The DNA in all cell types is identical. However, not all of this DNA is transcribed in all cells all the time. Only certain genes are activated and transcribed into mRNA and subsequently translated into protein or peptides. As mentioned previously, these gene products give the individual cell type its identity. Central to this regulation are protein:DNA interactions and protein:nutrient interactions. At initiation, basal transcription factors recognize and bind to the start site of the structural gene. They form a complex with RNA polymerase II, an enzyme that catalyzes the formation of mRNA. Transcription factors bind to particular base sequences, called response elements, in the promoter region of the DNA that are upstream of the transcription start site (Figure 2). Each gene promoter contains a characteristic array of response elements, and these will determine to which signals the particular gene responds. Transcription factors also bind nutrients, and it is here that some nutrients have their effects on gene expression.
The regulation of transcription often occurs through the regulation of transcription factors. These factors can be regulated by the rates of their synthesis or degradation, by phosphorylation or dephosphorylation, by ligand binding, by cleavage of a pro-transcription factor, or by release of an inhibitor. One class of transcription factors important for nutrition is the nuclear hormone receptor superfamily that is regulated by ligand binding. Ligands for these transcription factors include retinoic acid (the gene active form of vitamin A), fatty acids, vitamin D, thyroid hormone, and steroid hormones. These receptors are proteins with a series of domains. The retinoic acid receptor can serve as an example. Its ligand-binding domain recognizes and binds with high affinity the nutrient signal, retinoic acid. The DNA-binding domain gives gene specificity. It binds to a segment of the gene promoter that contains its corresponding response element, the retinoic acid response element (RARE). A transactivation domain then signals the effective occupation of this response element to the gene as a whole, including RNA polymerase II and its associated proteins. There are additional factors responsible for mediating this interaction between nutrient receptor and the transcription process. They include coactivating proteins, which stimulate transcription, and corepressor proteins, which can cause inhibition of transcription from a particular protein. In general, nutrients can signal the activation of transcription of some genes while at the same time turning off the transcription of others.
An interesting additional feature of this super-family of nuclear hormone receptors is that they contain two zinc atoms in their DNA-binding domains. Each zinc is bound by four cysteine residues and causes the folding of the protein in a finger-like shape that binds DNA. The zinc ion plays an important role in gene expression because of its central use in the zinc finger of a wide variety of DNA binding proteins. In the case of the receptor superfamily, although zinc is required for receptor function, there is no evidence that it plays a regulatory role. However, there are other transcription factors in which it does play a role. MTF-1 (metal response element (MRE)-binding transcription factor-1) responds to increasing zinc concentrations within the cell by translocating to the nucleus and activating the transcription of genes containing MREs in their promoter region. These genes include
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