8 Регуляция экспрессии генов. Система передачи сигнала (1160077), страница 7
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Posttranscriptional modification of mRNAsby processes such as differential splicing (p. 873) or RNA editing (seeBox 26-1) can affect which proteins are produced from an mRNA transcript and in what amounts. A variety of sequences can affect the rateat which an mRNA is degraded (p. 880). Many factors that affect therate at which an mRNA is translated into a protein, as well as theposttranslational modification and eventual degradation of that protein, were described in Chapter 26.Our primary focus in this chapter is the regulation of transcriptioninitiation (although some aspects of the regulation of translation will942Part IV Information PathwaysGeneDNA'TranscriptionPrimary transcript *V/VV/VPosttranscriptionalprocessingjNucleotidesmRNA degradationMature mRNATranslationProtein(inactive)Amino acidsPosttranslationalprocessingProtein degradationModifiedprotein(active)Figure 27-1 Six processes that affect the steadystate concentration of a protein.
Each of these processes is a potential point of regulation.be described). Of all the processes illustrated in Figure 27-1, regulation at the level of transcription initiation is the best documented andmay be the most common. At least one important reason is clear: as forall biosynthetic pathways, the most efficient place for regulation is thefirst reaction in the pathway. In this way, unnecessary biosynthesiscan be halted before energy is invested.
Transcription initiation also isan excellent point at which to coordinate the regulation of multiplegenes whose products have interdependent activities. For example,when DNA is heavily damaged, bacterial cells require a coordinatedincrease in the levels of many enzymes involved in DNA repair.Perhaps the most sophisticated form of coordination occurs in thecomplex regulatory circuits that guide the development of multicellulareukaryotes.In this chapter, we first describe the interactions between proteinsand DNA that are the key to transcriptional regulation. Specific proteins that regulate the expression of specific genes will then be discussed, first for prokaryotes and then for eukaryotes.
In the course ofthis discussion we will examine several different mechanisms by whichcells regulate gene expression and coordinate the expression of multiple genes.Chapter 27 Regulation of Gene Expression943Gene Regulation: Principles and ProteinsJust as the cellular requirements for different proteins vary, the mechanisms by which their respective genes are regulated also vary. Thedegree and type of regulation naturally reflect the function of the protein product of the gene. Some gene products are required all the timeand their genes are expressed at a more or less constant level in virtually all the cells of a species or organism. Many of the genes for enzymes that catalyze steps in central metabolic pathways such as thecitric acid cycle fall into this category.
These genes are often referred toas housekeeping genes. Constant, seemingly unregulated expression of a gene is called constitutive gene expression. The amounts ofother gene products rise and fall in response to molecular signals. Geneproducts that increase in concentration under prescribed molecularcircumstances are referred to as inducible, and the process of increasing the expression of the gene is called induction. The expression ofmany genes encoding DNA repair enzymes, for example, is induced inresponse to high levels of DNA damage.
Conversely, gene productsthat decrease in concentration in response to a molecular signal arereferred to as repressible, and the decrease in gene expression is calledrepression. For example, the presence of ample supplies of the aminoacid tryptophan leads to repression of the genes for the enzymes catalyzing tryptophan biosynthesis in bacteria.Transcription is mediated and regulated by protein-DNA interactions. The central component is RNA polymerase, an enzyme describedin some detail in Chapter 25. We begin here with a further descriptionof RNA polymerase from the standpoint of regulation, then proceed toa general description of the proteins that modulate the activity of RNApolymerase. Finally we discuss the molecular basis for the recognitionof specific DNA sequences by DNA-binding proteins.The Activity of RNA Polymerase Is RegulatedRNA polymerases bind to DNA and initiate transcription at specificsites in the DNA called promoters (Chapter 25).
Promoters generallyare found very near the position where RNA synthesis begins on theDNA template. The regulation of transcription initiation is, in effect,regulation of the interaction of RNA polymerase with its promoter.Promoters vary considerably in their nucleotide sequence, and thisaffects the binding affinity of RNA polymerases.
The binding affinity inturn affects the frequency of transcription initiation. In E. coli, somegenes are transcribed once each second whereas others are transcribedless than once per cell generation. Much of this variation is accountedfor simply by differences in promoter sequences. In the absence of regulatory proteins, differences in the sequences of two promoters mayaffect the frequency of transcription initiation by factors of 1,000 ormore.
Recall (see Fig. 25—5) that E. coli promoters have a consensussequence (Fig. 27-2). Promoters that exactly match the consensus se--35 region-10 regionRNA start siteDNA 5'mRNA\/\/\/VFigure 27-2 Consensus sequence for many E. colipromoters. N indicates any nucleotide. Most basesubstitutions in the -10 and -35 regions have anegative effect on promoter function. (Recall fromChapter 25 that by convention, DNA sequences areshown as they occur on the coding (nontemplate)strand.)944Part IV Information Pathwaysquence generally have the highest affinity for RNA polymerase and thehighest frequency of transcription initiation.
Mutations that change aconsensus base pair to a nonconsensus pair generally decrease promoter function: mutations that change a nonconsensus base pair to aconsensus pair usually enhance promoter function.Although housekeeping genes are expressed constitutively, theproteins they encode are present in widely varying amounts. For thesegenes the RNA polymerase-promoter interaction is the only factor affecting transcription initiation, and differences in promoter sequencesallow the cell to maintain the required level of each housekeepingprotein.Transcription initiation at the promoters of many genes that do notfall in the housekeeping category is further regulated in response tomolecular signals.
These promoters have a basal rate of transcriptioninitiation (determined by the promoter sequence), superimposed onwhich is regulation mediated by several types of regulatory proteins.These proteins affect the interaction between RNA polymerase and thepromoters.Transcription Initiation Is Regulated by ProteinsBinding to or near PromotersAt least three types of proteins regulate transcription initiation byRNA polymerase: (1) specificity factors alter the specificity of RNApolymerase for a given promoter or set of promoters; (2) repressorsbind to a promoter, blocking access of RNA polymerase to the promoter; (3) activators bind near a promoter, enhancing the RNApromoter interaction.We encountered prokaryotic specificity factors in Chapter 25, although they were not given that name.
The <x subunit (Mr 70,000)called a70 of the E. coli RNA polymerase holoenzyme is a prototypicalspecificity factor that mediates specific promoter recognition and binding. Under some conditions, notably when the bacteria are subjected toheat stress, cr70 is replaced with another specificity factor (Mr 32,000)called a32 (p. 863). When bound to a32, RNA polymerase does not bindto the standard E. coli promoters (Fig.
27-2), but instead is directed toa specialized set of promoters with the sequence structure shown inFigure 27-3. The promoters control the expression of a set of genesthat make up the heat-shock response. Altering the polymerase to direct it to different promoters is one mechanism by which a set of related genes can be coordinately regulated. Other mechanisms will beencountered throughout this chapter.Figure 27—3 Consensus sequence for promotersthat regulate the expression of genes involved inthe heat-shock response in E. coli.
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