Science at the Frontier (1992) / Chapter Skim
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5 Gene Regulation: Gene Control: Transcription Factors and Mechanisms
5 Gene Regulation: Gene Control: Transcription Factors and Mechanisms
Pages 94-118
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From page 94... ...
One of the most intriguing questions involves the very first step in the process, how the DNA itself delivers its information to the organism. At the Frontiers symposium, a handful of leading genetic scientists talked about their research on transcription the crucial first stage in which RNA molecules are formed to deliver the DNA's instructions to a cell's ribosomal protein production factories.
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From page 95... ...
Intrinsic to the structure of the DNA molecule are very long strings composed of so-called base pairs, of which there are four types. A gene is a segment of this string that has a particular sequence of the four base pairs, giving it a unique character.
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From page 96... ...
Because that structure facilitates DNA's role and function to such an extent that the whole process of decoding and eventually altering the basic genetic information was suddenly glimpsed by drawing the curtain back on what has come to be known as the alphabet of life. · The structure of DNA was at once realized to be dramatically suggestive of how the molecule actually functions to store and deliver coded information.
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From page 97... ...
The explanation remains an interesting question, and so far the best guess seems to be the redundancy-as-error-protection theory: that for certain amino acids, codons that can be mistaken in a "typographical mistranslation" will not so readily produce a readout error, because the same result is called for by several codons. · The codons serve, said Hanahan "to transmit the protein coding information from the site of DNA storage, the cell's nucleus, to the site of protein synthesis, the cytoplasm.
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From page 98... ...
molecule. When base pairing occurs, an amino acid carried at the other end of the tRNA molecule is added to the growing protein chain.
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From page 99... ...
. Tjian's overview, "Gene Regulation in Animal Cells: Transcription Factors and Mechanisms," touched on much of the above background and presented some of the basic issues scientists are exploring as they probe the mRNA process.
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From page 100... ...
"noncoding" portion of the human genome. Mapping is one thing: eventually with the aid of supercomputers and refined experimental and microscopy techniques to probe the DNA material, an army of researchers will have diagrammed a map that shows the generic, linear sequence of all of the nucleotide base pairs, which number about 3 billion in humans.
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From page 101... ...
But the transcript made at the first step is understandably critical, because somehow the proper part of the enormous DNA master plan the correct gene or sequence of genes must be accessed, consulted, and translated for transmission to the next step. Thus the major questions of transcription often referred to as gene expression draw the attention of some of the world's leading geneticists, including Tjian and his colleagues at the symposium's gene regulation session, who explained how they probe the mRNA process experimentally in search of answers.
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From page 102... ...
~ EUCARYOTE ' FIGURE 5.3 (Top) Pathway for the flow of genetic information referred to in 1956 by Francis Crick as the central dogma.
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From page 103... ...
TRANSCRIPTION FACTORS Tjian believes the key to unravelling the complexities of the code lies in understanding how the messenger RNA transcript is crafted. Since the chemical rules by which RNA polymerase operates are fairly well understood, he is looking for more subtle answers, related to how the protein finds the proper part or parts of the genome that is, the gene or genes that need to be consulted at the moment.
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From page 104... ...
The DNA molecule in a eukaryote is wrapped up in a complex of proteins called histones, which have to be cleared off the DNA template. Then the two complementary strands are locally unwound, and the RNA polymerase starts to move along one strand to create the transcript.
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From page 105... ...
As Tjian put it, "RNA polymerase is rather promiscuous" and not capable of discriminating discrete parts of the genome. It is the transcription factors that "seem to be designed to recognize very subtle differences in the DNA sequence of the template and can easily discriminate a real piece of information from junk.
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From page 106... ...
The experimental goal is to elucidate in the DNA sequence a so-called promoter region—the "punctuation mark," he explained, "which instructs transcription factors and RNA polymerase where to begin transcribing the DNA." Because "some of these control regions that tell the polymerase where to initiate are very much simplified compared to the control regions you find for cellular genes," Berk has been able to home in on the promoter region for the E1B transcription unit. This process illustrates one of the basic genetic engineering protocols.
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From page 107... ...
After some years now of experience with binding studies, Tjian and other molecular biologists have begun to recognize certain signatures, structures that seem to indicate transcription factor binding domains. One of the most prominent are the so-called zinc fingers, actually a specific grouping of amino acids that contains a zinc molecule located between cysteine and histidine residues.
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From page 108... ...
turns out," Struhl pointed out, "the basic rules of how transcription works are really fundamentally the same in yeast and in humans and all eukaryotic species." One genetic approach researchers have used in yeast to try to identify some of the key proteins involved in transcription involves isolating mutants whose properties differ in some respect from those of the normal organism. "In yeast cells," he explained, "one can easily isolate mutants that do or do not grow under certain circumstances....
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From page 109... ...
In addition, a protein that is synthesized in a test tube can also be treated with radioactive label, which in turn enables many interesting related experiments. A final technique mentioned by Struhl is used to figure out how much information there is in a particular genetic function, or, more specifically, how much DNA a specific DNA-binding protein actually recognizes," and what, really, is being recognized.
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From page 110... ...
Once bound to the right part of the genome, they must program the RNA polymerase and the transcriptional accessory proteins to then begin RNA synthesis," and to do so, moreover, with exquisite temporal finesse. Experiments indicate that an altogether different part, as Tjian puts it, "the other half" of the transcription factor protein, does this, probably by direct protein-to-protein interaction, triggering regulation on or off, up or down.
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From page 111... ...
The TATA box-binding protein alights first on the gene, and then another specific molecule comes along, and then another, in a characteristic sequence, until what Tjian called the "basic machinery," or basal complex, has been assembled. From this point onward in the transcription process, each gene likely has a specific and unique scenario for attracting specific proteins and transcription factors, but will already have constructed the generic, basal complex to interact chemically with them (Figure 5.6~.
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From page 112... ...
to recruit the basal initiation factors. This model shows the tethering factor interacting with the TATA binding factor TFIID since its function replaces the TATA box and it copurifies with TFIID.
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From page 113... ...
Several of the session's scientists described how genetics makes creative use of recombinant DNA technology to alter and study the expression of genes in the embryo and the developing organism. Transcription factors are proteins that tend to influence the expression of genes in the mRNA stage.
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From page 114... ...
"Often," he said, "the properties of individual cell systems are only discernible by studying disruptions in their functions, whether natural or induced." He is exploring abnormal development and disease, primarily cancer, using transgenic mice that pass on to newborn progeny an altered piece of DNA especially crafted by the genetic scientist in vitro. The next generation of animals can then be studied as the genetic expression of the altered DNA plays itself out over time during developmentboth in embryogenesis and as the animal matures.
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From page 115... ...
Next, he removes fertilized eggs from a normal mouse, introduces his hybrid gene with a very fine capillary pipette, and then reimplants this injected embryo back into a foster mother that goes on to give birth to what is defined as a transgenic mouse, that is, one that is carrying an artificially created gene. When the transgenic mouse mates with a normal mouse, about half of the second-generation mice inherit a set of DNA that now includes this new gene, still recognized by its regulatory information as a normal gene but whose protein instructions code for cancer growth.
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From page 116... ...
Many of the transcription factors have a role in regulating protein production. Many of these same transcription factors can act as oncogenes.
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From page 117... ...
One particular protein is called APT, which in other studies has been revealed as an oncogene. Said Tjian: "Nuclear transcription factors are also nuclear oncogenes.
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From page 118... ...
1990. RNA polymerase B (II)
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