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Attenuation, Control of Gene Expression By: Advanced Article
Attenuation, Control of Gene Expression By: Advanced Article
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Article Contents
Transcription Attenuation Mediated by Ribosomes Transcription Termination Mediated by a Translating Ribosome Transcription Antitermination Mediated by a Translating Ribosome Transcription Attenuation Mediated by Proteins Transcription Termination Mediated by an RNA Binding Protein Transcription Antitermination Mediated by an RNA Binding Protein Transcription Attenuation Mediated by RNA Transcription Termination Mediated by an RNA Molecule Transcription Antitermination Mediated by an RNA Molecule Transcription Attenuation Mediated by Metabolites Transcription Termination Mediated by a Small Metabolite Transcription Antitermination Mediated by a Small Metabolite Concluding Remarks
The Pennsylvania State University, University Park, Pennsylvania Department of Biological Science, State University at Buffalo,
Bacteria use a variety of strategies to regulate transcription elongation in response to changes in their environment. Several of these regulatory events are classied as transcription attenuation mechanisms, which involve regulated transcription termination to control expression of downstream genes. In most cases, two alternative RNA secondary structures, an antiterminator and an intrinsic terminator, share nucleotides in common such that their formation is mutually exclusive. Thus, the level of expression of the downstream genes depends on the frequency that the antiterminator forms in the nascent transcript. Transcription attenuation mechanisms in general are separated into two categories. The rst category involves situations in which the action of a regulatory molecule promotes transcription termination, with the default situation being transcription readthrough. The second category involves situations in which the action of the regulatory molecule promotes transcription readthrough (antitermination), with the default situation being transcription termination. Transcription attenuation controls the expression of several amino acid biosynthetic and catabolic operons. These mechanisms are often controlled by the efciency of leader peptide synthesis in Gram-negative bacteria, whereas Gram-positive organisms often use RNA binding proteins or tRNA molecules to determine whether the RNA will fold into the antiterminator or terminator structures. Several examples of transcription attenuation also exist in which an antisense RNA is responsible for controlling plasmid copy number. In addition, small metabolites participate in transcription attenuation mechanisms of a wide variety of bacterial genes by binding directly to the nascent transcript.
The ability of organisms to regulate gene expression in response to environmental signals is vital for their survival. Virtually every step involved in the synthesis, function, and degradation of macromolecules is a potential target for one or more regulatory events (reviewed in References 13). Several regulatory events that occur after transcription initiates are categorized as transcription attenuation mechanisms in which the extent of transcription termination is modulated to control the expression of downstream genes. Transcription attenuation allows the organism to modulate the extent of transcription readthrough past the terminator in response to changing environmental signals, thereby regulating expression of the downstream genes. Transcription attenuation mechanisms in general are divided into two categories. In one case, the default situation is transcription
readthrough; the action of a regulatory (effector) molecule promotes termination. The default situation for the second category is transcription termination. In this case, the action of an effector molecule promotes transcription readthrough (antitermination) (1, 2). In each case, the genetic information required for transcription attenuation is encoded within a leader region located between the transcription start site and the rst structural gene of the operon or between two genes within an operon (reviewed in Reference 4). This article is organized around the class of effector molecule that is used to sense environmental changes. These regulatory factors can be translating ribosomes, proteins, RNA molecules, or metabolites (Fig. 1). Examples are known in which each class of effector molecule promotes transcription termination or antitermination. One example of each of these 1
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RNAP (b)
Figure 1 Generalized model for sensing regulatory effectors by nascent mRNA leader transcripts. Transcription attenuation mechanisms have been identied in which the nascent transcript interacts with a translating 70 S ribosome, a protein, an RNA molecule or a small metabolite. (a) Binding of the effector molecule promotes transcription termination. (b) Binding of the effector molecule promotes transcription readthrough (antitermination). See text for details.
general regulatory mechanisms is described in detail, whereas additional examples are included to illustrate particularly important points. A common theme that will emerge throughout this article is that synchronization of factor binding and/or RNA folding with RNA polymerase (RNAP) position is critical in all transcription attenuation mechanisms.
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AUG
1 2 RNAP
70S RNAP AUG Limiting Trp Antiterminator 70S UGG UGG 1 2 3 70S RNAP UGA 2 3 4 UUUU Termination (a) Pause Hairpin Excess Trp Terminator RNAP
4 Readthrough
AUG
RNAP
70S UGA
Figure 2 (a) Transcription attenuation model of the E. coli trpEDCBA operon. RNAP pauses after formation of the pause hairpin (stem-loop 1:2). RNAP pausing provides time for a ribosome to initiate translation of the leader peptide. In tryptophan-limiting conditions, the ribosome stalls at one of the tandem Trp codons, which thereby allows formation of the antiterminator structure (stem-loop 2:3), which results in transcription readthrough. In conditions of tryptophan excess, the ribosome reaches the leader peptide stop codon and dissociates. In this instance, formation of the anti-antiterminator blocks formation of the antiterminator, which thereby allows formation of the terminator hairpin (stem-loop 3:4), which causes transcription to terminate upstream from the trp operon structural genes. See text for details. [Adapted from the Encyclopedia of Molecular Biology (1999) with permission (1).] (b) Antitermination model of E. coli tnaCAB operon. RNAP pauses after formation of the pause hairpin. RNAP pausing provides time for a ribosome to initiate translation of the leader peptide. Under noninducing conditions (free tryptophan is not in excess), dissociation of the 70 S ribosome at the tnaC stop codon exposes a rut site allowing Rho binding. Rho translocates to paused RNAP leading to transcription termination. Under inducing conditions (excess tryptophan), the combination of tryptophan binding and nascent peptide interaction with the ribosome exit channel causes the ribosome to stall at the tnaC stop codon because the nascent peptide cannot be cleaved from the peptidyl-tRNA. The stalled ribosome prevents Rho from binding to the nascent transcript that leads to transcription readthrough. Tryptophan is represented by a star. See text for details. [Adapted from the Encyclopedia of Molecular Biology (1999) with permission (2).]
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corresponding mechanisms are remarkably similar to those described above. One clear distinction that is worthy of particular mention is that the mechanisms that rely on RNA binding proteins do not require coupling of transcription and translation. As a consequence, this general regulatory strategy has been identied in several eukaryotic organisms in which transcription and translation occur in separate cellular compartments (reviewed in Reference 3).
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5 Stem-loop
Pause Hairpin
RNAP Limiting Trp Antiterminator 5 Stem-loop 5 Stem-loop 1 1 2 RNAP 3 Readthrough (a) Limiting b -glucosides Terminator G P P G 1 2 3 RNAP G G 1 2 RNAP 3 Readthrough (b)
Figure 3 (a) Transcription attenuation model for the B. subtilis trpEDCFBA operon. RNAP pauses after formation of the pause hairpin. RNAP pausing may provide additional time for tryptophan-activated TRAP to bind to the nascent transcript. In tryptophan-limiting conditions, TRAP does not bind to the 5 SL or the (G/U)AG repeats (small black rectangles). Thus, formation of the antiterminator (stem-loop 1:2) results in transcription readthrough. In conditions of tryptophan excess, tryptophan-activated TRAP binds to the 5 SL and the triplet repeats. Bound TRAP blocks or disrupts formation of the antiterminator structure, which thereby allows formation of the terminator hairpin (stem-loop 2:3), which causes transcription to terminate upstream from the trp operon structural genes. See text for details. (b) Antitermination model for the E. coli bglGFB operon. Under noninducing conditions (limiting -glucosides), the phosphorylated BglG monomers cannot bind to the nascent transcript. Thus, formation of a terminator hairpin (stem-loop 2:3) causes transcription to terminate. In the presence of -glucosides, the BglG monomers are dephosphorylated, which allows them to dimerize. BglG dimers bind and stabilize the antiterminator structure (stem-loop 1:2), which prevents formation of the overlapping terminator, and transcription continues into the structural genes. Note that overlapping antiterminator and terminator hairpins are found in the leader region and between the bglG and the bglF coding sequences. See text for details.
Excess Trp
Terminator RNAP
2 TRAP
UUUU
Termination
UUUU
Termination
containing 4 -strands from one subunit and 3 -strands from the adjacent subunit. L-tryptophan binds between each adjacent subunit with the indole ring buried in a hydrophobic pocket. Nine hydrogen bonds are formed among the amino group, the carboxyl group, and the indole nitrogen of each bound tryptophan, with amino acids residing in two loops on adjacent subunits. The hydrogen bonds formed among Thr30, Gln47, and Thr49 and tryptophan are essential for TRAP function. Conversely, the hydrogen bond between Ser53 and the carboxyl group of tryptophan is dispensable for TRAP activity (26). The mechanism of TRAP activation by tryptophan is not known because the structure of nonliganded TRAP (apo-TRAP) has not been determined, although it is known that tryptophan binding is not required for oligomerization of the protein (27). NMR studies of TRAP in both the nonliganded and the activated states demonstrate that apo-TRAP is more exible than the tryptophan-activated protein (28), which imply that reduced exibility plays an important role in altering the RNA binding activity of TRAP.
Four amino acid residues within each TRAP subunit (E36, K37, K56, and K58) are critical for RNA binding (29). Three of these residues form KKR motifs that are aligned on the perimeter of the B. subtilis and the homologous B. stearothermophilus TRAP ring. Several crystal structures of B. stearothermophilus TRAPRNA complexes show that the RNA wraps around the TRAP protein ring with the bases pointing toward the protein, such that the majority of the hydrogen bond interactions are with the RNA bases and there are no contacts to phosphates (21, 30). The only direct hydrogen bond to the RNA backbone is to the 2 OH of the ribose of the third G in each repeat. K37 forms a hydrogen bond with the A of each GAG repeat, whereas K56, R58, and E36 hydrogen bond with the G in the third position of each repeat. The side chain of K37 also forms hydrophobic interactions with the base in the rst residue of each repeat. The spacer bases do not make specic contacts with TRAP, which is consistent with the lack of sequence conservation in spacers of natural TRAP binding sites and with ndings that indicate that their composition in general is not critical for TRAP binding. 5
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A model of TRAP-trp leader RNA interaction that encompasses several recent ndings is as follows. Once a sufcient number of triplet repeats emerge from RNAP (e.g., three or four repeats), TRAP binds to the nascent trp leader transcript by contacting the 5 SL and the emerging triplet repeats. The nature of these contacts orients the protein so the RNA easily can wrap around TRAPs periphery as transcription continues. TRAP sequesters the remaining repeats in a 5 to 3 directionality as they emerge from RNAP (31, 32). As the tenth and eleventh repeats bind, the 5 SL is displaced as a consequence of the geometry of the TRAPRNA complex in which TRAP completely is encircled by RNA (24). In conjunction with RNAP pausing, this RNA binding mechanism ensures that TRAP binds in time to block formation of the antiterminator structure.
subsequently to -glucosides. It seems that BglF recruits BglG to the cell membrane in the absence of -glucosides such that the system can respond rapidly to the presence of the stimulating sugar (35). Expression of two sucrose utilization operons in B. subtilis , sacPA and sacB , is induced by sucrose by similar transcription antitermination mechanisms; antitermination is mediated by the RNA binding proteins SacT and SacY, respectively (33). The structure of the RNA binding domain of SacY has been solved by both NMR (36) and X-ray crystallography (37). The domain exists as a dimer with each monomer consisting of a four-stranded antiparallel -sheet. The structure of the RNA-binding domain from the LicT antiterminator protein in complex with a 29 base RNA shows that LicT binds mostly through hydrophobic and stacking interactions with the RNA and that binding clamps the RNA so as to stabilize the antiterminator structure (38).
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UUUU
Termination
Antiterminator
RNAP
3 Readthrough (a)
2 RNAP
2 1
RNAP
UUUU
Termination (b)
3 Readthrough
Figure 4 (a) Transcription attenuation model of S. agalactiae plasmid pIP501-encoded repR. When the concentration of RNA III is low, the absence of RNA III interaction allows formation of the antiterminator structure (stem-loop 1:2), which blocks formation of the terminator that leads to transcription readthrough. When RNA III is abundant, the kissing loop interaction between loops L III and L IV of RNA III with loops L I and L II within the nascent RNA II (repR) transcript blocks formation of the antiterminator, which promotes formation of the terminator hairpin (stem-loop 2:3) and transcription termination in the repR leader region. The positions of the residues that correspond to L II of RNA II (stem-loop A:B) are included in each structure for clarity. See text for details. [Adapted from the Encyclopedia of Molecular Biology (1999) with permission (1).] (b) General T-box model of tRNA-mediated antitermination. Under excess amino acid conditions, the amino acid on charged tRNA does not allow interaction of the tRNA with the discriminator sequence in the nascent transcript. As a consequence, formation of the terminator (stem-loop 2:3) halts transcription in the leader region. Under limiting amino acid conditions, uncharged tRNA binds to the nascent transcript via anticodon-specier sequence base pairing as well as by base pairing between the 3 end of tRNA and the discriminator region. This second interaction stabilizes the antiterminator structure (stem-loop 1:2), which results in transcription readthrough. The tRNA is shown as a cloverleaf structure, and a boxed A.A. attached to the tRNA indicates it is aminoacylated. See text for details. (Adapted from Reference 45 with permission.)
II and I of RNA II, respectively (42). Moreover, loop L1 of RNA II contains a YUNR (Y = C or U; N = A, C, G or U; R = A or G) U-turn motif that is important for the kissing interaction; mutations that disrupt the U-turn motif result in higher plasmid copy number (43). Although RNA III and RNA II share extensive sequence complementarity, complete pairing is not necessary to promote transcription termination of RNA II. The nding that inhibition of transcription readthrough is considerably faster than stable complex formation suggests that inhibition precedes stable pairing (41). Furthermore, complete pairing only occurs at a low frequency because pairing of
complementary folded RNAs often arrests at the stage of stable binding intermediates (41).
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Most of these genes are from Gram-positive bacteria, although a few examples have been identied in Gram-negative organisms as well (reviewed in References 44 and 45). Expression of these genes is induced specically by starvation for the cognate amino acid. A generalized model of the T-box antitermination mechanism is shown in Fig. 4b. The untranslated leader region of each operon contains several conserved structural elements preceding an intrinsic transcription terminator. When the amino acid pool in the cell is sufciently high, transcription terminates prematurely in the leader region upstream from the coding sequences. In addition to the conserved secondary structures, a critical 14-nt sequence called the T box is present in each leader region. Another structure of the leader region, which forms when the T-box base pairs with the 5 side of the terminator stem, functions as an antiterminator, which allows transcription to read through into the structural genes (46). Another critical feature of the leader region of T-boxcontrolled genes is a trinucleotide sequence that corresponds to a codon for the appropriate amino acid involved in regulating each operon. For example, in tyrS , which encodes tyrosyl-tRNA synthetase, the leader contains a UAC tyrosine codon (46). This codon-like sequence is always present within an internal loop of a conserved RNA structure. This triplet is designated the specier sequence because it specically interacts with the anticodon of the cognate tRNA. A second base pairing interaction between the acceptor end of uncharged tRNA and the complementary sequence in the T box leads to stabilization of the antiterminator structure. The antiterminator side bulges contain a UGGN sequence, where N corresponds to a variable T-box position that covaries with the residue preceding the CCA acceptor end of the cognate tRNA (47, 48). The presence of the amino acid on charged tRNA prevents this second interaction from taking place (49). Although tRNA interaction with the specier and UGGN sequences are rmly established, substantial genetic data suggest that additional tRNAmRNA contacts take place (44). Reconstitution of the B. subtilis glyQS T-box mechanism in vitro with puried components suggests that additional protein factors are not required for tRNA-mediated antitermination (50). Furthermore, the nding that charged tRNA can compete with uncharged tRNA for mRNA binding indicates that the ratio of uncharged:charged tRNA is monitored by the nascent transcript, rather than simply the concentration of uncharged tRNA (49). Although codonanticodon interaction takes place at least 100 nt upstream from the terminator, nascent transcripts that extend just upstream of the terminator are still competent for tRNA binding and antitermination (49). Thus, it is possible that RNAP pausing participates in this regulatory mechanism by providing additional time for tRNA binding, although a regulatory pausing event has not been rmly established (51). Under starvation conditions for the corresponding amino acid, the ratio of uncharged-to-charged tRNA is relatively high. In this case, efcient interaction of uncharged tRNA with both the specier and the discriminator sequence elements of the nascent leader transcript promotes formation of the antiterminator structure, which allows transcription to proceed into the coding region. The resulting increase in the level of 8
tRNA synthetase presumably allows more efcient charging of the scarce amino acid. As the concentration of the amino acid increases, an increasing proportion of nascent transcripts will interact with charged tRNA. In these instances, formation of the terminator hairpin will cause RNAP to terminate transcription in the leader region.
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Limiting SAM
Antiterminator
3 4
UUUU Termination
UUUU
Termination
purine analogs. This nding supports a model in which regulation depends on the kinetics of ligand binding and the rate of transcription, rather than simple binding afnity (67). The structure of the pbuE leader RNA is similar to the guanine-dependent RNA sensor in the xpt leader transcript (65). It was shown that a single C to U substitution in the loop of a triple helical junction swapped the xpt aptamer specicity from guanine to adenine. Importantly, the pbuE leader contains a U in the identical position. These results led to the hypothesis that this U residue in the pbuE leader base-paired with adenine, whereas the C residue in the xpt transcript paired with guanine This hypothesis was veried by NMR structural studies. Moreover, it was determined that adenine binding to pbuE leader RNA involved a base triple with two U residues, which includes the previously proposed uridine (68).
Concluding Remarks
The discovery of transcription attenuation over 30 years ago led to the realization that mRNAs serve a purpose beyond simply functioning as a conduit of information from DNA to protein. Indeed, the discovery of transcription attenuation established for the rst time that RNA structure can modulate gene expression. It is now abundantly clear that expression of many genes is controlled by several different mechanisms after transcription 9
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initiates. Furthermore, it is apparent that transcription attenuation occurs by a variety of mechanisms that differ in the nature of the effector molecule (translating ribosome, RNA binding protein, RNA molecule, small metabolite), whether the effector promotes transcription termination (attenuation) or transcription readthrough (antitermination), as well as the structure of the RNA target in the nascent transcript. Although each mechanism described in this review contains key differences, it is also apparent that all but one of these mechanisms share an important feature: the presence of mutually exclusive antiterminator and terminator structures. One point of view is that these RNA-based regulatory mechanisms are relics of an RNA world in which both the storage of genetic information and the metabolic function were carried out by RNA molecules. Conversely, it is conceivable that these regulatory mechanisms have evolved more recently. In either case, it is apparent that what was once viewed as a biologic quirk is widespread and has been adapted to suit the physiologic needs of perhaps every organism.
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Acknowledgments
The authors thank the members of their laboratories, both past and present, for stimulating discussion and discovery. This work was supported by grants GM052840 to P. B. and GM062750 to P.G. from the National Institutes of Health.
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Further Reading
Weisberg RA, Gottesman ME. Processive antitermination. J. Bacteriol. 1999;181:359367. This excellent review article summarizes the mechanisms responsible for processive antitermination in lambdoid bacteriophages, which includes the classic N-mediated antitermination of lambda and factor-independent antitermination of the related HK022 phage. This work was not included in this article because of space considerations.
See Also
mRNA Untranslated Regions (UTRs) Protein-Nucleic Acid Interactions Small Molecule-Nucleic Acid Interactions Transcription, Activators and Repressors of Transcription, Initiation of
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WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.