Essential Cell Biology 5th edition
242 CHAPTER 7 From DNA to Protein: How Cells Read the Genome2 µmFigure 7–24 RNAs are produced byfactories within the nucleus. RNAs aresynthesized and processed (red) andDNA is replicated (green) in intracellularECB5 m6.47/7.24condensates that form discretecompartments within a mammalian nucleus.In this micrograph, these loose aggregatesof protein and nucleic acid were visualizedby detecting newly synthesized DNA andRNA. In some instances, both replicationand transcription are taking place at thesame site (yellow). (From D.G. Wansinket al., J. Cell Sci. 107:1449−1456, 1994.With permission from The Company ofBiologists.)RNA Synthesis and Processing Takes Place in “Factories”Within the NucleusRNA synthesis and processing in eukaryotes requires the coordinatedaction of a large number of proteins, from the RNA polymerases andaccessory proteins that carry out transcription to the enzymes responsiblefor capping, polyadenylation, and splicing. With so many componentsrequired to produce and process every one of the RNA molecules that arebeing transcribed, how do all these factors manage to find one another?We have already seen that the enzymes responsible for RNA processingride on the phosphorylated tail of eukaryotic RNA polymerase II as it synthesizesan RNA molecule, so that the RNA transcript can be processedas it is being synthesized (see Figure 7–16). In addition to this association,RNA polymerases and RNA-processing proteins also form loosemolecular aggregates—generally termed intracellular condensates—thatact as “factories” for the production of RNA. These factories, which bringtogether the numerous RNA polymerases, RNA-processing components,and the genes being expressed, are large enough to be seen microscopically(Figure 7−24).The aggregation of components needed to perform a specific task is notunique to RNA transcription. Proteins involved in DNA replication andrepair also converge to form functional factories dedicated to their specifictasks. And genes encoding ribosomal RNAs cluster together in thenucleolus (see Figure 5−17), where their RNA products are combinedwith proteins to form ribosomes. These ribosomes, along with the maturemRNAs they will decode, must then be exported to the cytosol, wheretranslation will take place.Mature Eukaryotic mRNAs Are Exported from the NucleusOf all the pre-mRNA that is synthesized by a cell, only a small fraction—the sequences contained within mature mRNAs—will be useful. Theremaining RNA fragments—excised introns, broken RNAs, and aberrantlyspliced transcripts—are not only useless, but they could be dangerous tothe cell if allowed to leave the nucleus. How, then, does the cell distinguishbetween the relatively rare mature mRNA molecules it needs toexport to the cytosol and the overwhelming amount of debris generatedby RNA processing?The answer is that the transport of mRNA from the nucleus to the cytosolis highly selective: only correctly processed mRNAs are exported andtherefore available to be translated. This selective transport is mediatedby nuclear pore complexes, which connect the nucleoplasm with thecytosol and act as gates that control which macromolecules can enteror leave the nucleus (discussed in Chapter 15). To be “export ready,” anmRNA molecule must be bound to an appropriate set of proteins, eachof which recognizes different parts of a mature mRNA molecule. Theseproteins include poly-A-binding proteins, a cap-binding complex, andproteins that bind to mRNAs that have been appropriately spliced (Figure7–25). The entire set of bound proteins, rather than any single protein,ultimately determines whether an mRNA molecule will leave the nucleus.The “waste RNAs” that remain behind in the nucleus are degraded there,and their nucleotide building blocks are reused for transcription.mRNA Molecules Are Eventually Degraded in the CytosolBecause a single mRNA molecule can be translated into protein manytimes (see Figure 7–2), the length of time that a mature mRNA moleculepersists in the cell greatly influences the amount of protein it produces.
From RNA to Protein243nuclearenvelopeexonjunctioncomplexcap-bindingprotein5′ capinitiation factorsTRANSLATIONfor protein synthesisAAAAAApoly-A-bindingproteinnuclear porecomplexAAAAAANUCLEUSCYTOSOLPROTEINEXCHANGEAAAAAAAFigure 7–25 A specialized set of RNA-binding proteins signals that a completed mRNA is ready for exportto the cytosol. As indicated on the left, the 5’ cap and poly-A tail of a mature mRNA molecule are “marked” byproteins that recognize these modifications. Successful splices are marked by exon junction complexes (see Figure7−22). Once an mRNA is deemed “export ready,” a nuclear transport receptor (discussed in Chapter 15) associateswith the mRNA and guides it through the nuclear pore. In the cytosol, the mRNA can shed some of these proteinsand bind new ones, which, along with poly-A-binding protein, act as initiation factors for protein synthesis, as wediscuss in the next section of the chapter. ECB5 e7.23/7.25Each mRNA molecule is eventually degraded into nucleotides by ribonucleases(RNAses) present in the cytosol, but the lifespans of mRNAmolecules differ considerably—depending on the nucleotide sequence ofthe mRNA and the type of cell. In bacteria, most mRNAs are degradedrapidly, having a typical lifespan of about 3 minutes. The mRNAs in eukaryoticcells usually persist longer: some, such as those encoding β-globin,have lifespans of more than 10 hours, whereas others stick around forless than 30 minutes.These different lifespans are in part controlled by nucleotide sequencesin the mRNA itself, most often in the portion of RNA called the 3ʹ untranslatedregion, which lies between the 3ʹ end of the coding sequence andthe poly-A tail (see Figure 7−17). The lifespans of different mRNAs helpthe cell control how much protein will be produced. In general, proteinsmade in large amounts, such as β-globin, are translated from mRNAsthat have long lifespans, whereas proteins made in smaller amounts, orwhose levels must change rapidly in response to signals, are typicallysynthesized from short-lived mRNAs.The synthesis, processing, and degradation of RNA in eukaryotes andprokaryotes is summarized and compared in Figure 7−26.FROM RNA TO PROTEINBy the end of the 1950s, biologists had demonstrated that the informationencoded in DNA is copied first into RNA and then into protein. The debatethen shifted to the “coding problem”: How is the information in a linearsequence of nucleotides in an RNA molecule translated into the linearsequence of a chemically quite different set of subunits—the amino acidsin a protein? This fascinating question intrigued scientists from many differentdisciplines, including physics, mathematics, and chemistry. Herewas a cryptogram set up by nature that, after more than 3 billion yearsof evolution, could finally be solved by one of the products of evolution—the human brain! Indeed, scientists have not only cracked the code buthave revealed, in atomic detail, the precise workings of the machinery bywhich cells read this code.
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From RNA to Protein
243
nuclear
envelope
exon
junction
complex
cap-binding
protein
5′ cap
initiation factors
TRANSLATION
for protein synthesis
AAAAAA
poly-A-binding
protein
nuclear pore
complex
AAAAAA
NUCLEUS
CYTOSOL
PROTEIN
EXCHANGE
AAAAAAA
Figure 7–25 A specialized set of RNA-binding proteins signals that a completed mRNA is ready for export
to the cytosol. As indicated on the left, the 5’ cap and poly-A tail of a mature mRNA molecule are “marked” by
proteins that recognize these modifications. Successful splices are marked by exon junction complexes (see Figure
7−22). Once an mRNA is deemed “export ready,” a nuclear transport receptor (discussed in Chapter 15) associates
with the mRNA and guides it through the nuclear pore. In the cytosol, the mRNA can shed some of these proteins
and bind new ones, which, along with poly-A-binding protein, act as initiation factors for protein synthesis, as we
discuss in the next section of the chapter. ECB5 e7.23/7.25
Each mRNA molecule is eventually degraded into nucleotides by ribonucleases
(RNAses) present in the cytosol, but the lifespans of mRNA
molecules differ considerably—depending on the nucleotide sequence of
the mRNA and the type of cell. In bacteria, most mRNAs are degraded
rapidly, having a typical lifespan of about 3 minutes. The mRNAs in eukaryotic
cells usually persist longer: some, such as those encoding β-globin,
have lifespans of more than 10 hours, whereas others stick around for
less than 30 minutes.
These different lifespans are in part controlled by nucleotide sequences
in the mRNA itself, most often in the portion of RNA called the 3ʹ untranslated
region, which lies between the 3ʹ end of the coding sequence and
the poly-A tail (see Figure 7−17). The lifespans of different mRNAs help
the cell control how much protein will be produced. In general, proteins
made in large amounts, such as β-globin, are translated from mRNAs
that have long lifespans, whereas proteins made in smaller amounts, or
whose levels must change rapidly in response to signals, are typically
synthesized from short-lived mRNAs.
The synthesis, processing, and degradation of RNA in eukaryotes and
prokaryotes is summarized and compared in Figure 7−26.
FROM RNA TO PROTEIN
By the end of the 1950s, biologists had demonstrated that the information
encoded in DNA is copied first into RNA and then into protein. The debate
then shifted to the “coding problem”: How is the information in a linear
sequence of nucleotides in an RNA molecule translated into the linear
sequence of a chemically quite different set of subunits—the amino acids
in a protein? This fascinating question intrigued scientists from many different
disciplines, including physics, mathematics, and chemistry. Here
was a cryptogram set up by nature that, after more than 3 billion years
of evolution, could finally be solved by one of the products of evolution—
the human brain! Indeed, scientists have not only cracked the code but
have revealed, in atomic detail, the precise workings of the machinery by
which cells read this code.