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Principles of Translational Control: An Overview

John W.B. Hershey1, Nahum Sonenberg2, and Michael B. Mathews3

1Department of and Molecular , School of Medicine, University of California, Davis, California 95616 2Department of Biochemistry and Goodman Cancer Research Center, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada 3Department of Biochemistry and , UMDNJ—New Jersey Medical School, Newark, New Jersey 07103-2714 Correspondence: [email protected]; [email protected]; [email protected]

Translational control plays an essential role in the regulation of expression. It is espe- cially important in defining the proteome, maintaining homeostasis, and controlling cell proliferation, growth, and development. Numerous disease states result from aberrant regu- lation of synthesis, so understanding the molecular basis and mechanisms of trans- lational control is critical. Here we outline the pathway of protein synthesis, with special emphasis on the initiation phase, and identify areas needing further clarification. Features of translational control are described together with numerous specific examples, and we discuss prospects for future conceptual advances.

rotein synthesis is an indispensable process controlling their mRNA translational efficien- Pinthe pathwayof ,andis akey cies and protein degradation rates. During early component in its control. Regulation of trans- stages of viral infection (Walshet al. 2012) and in lation plays a prominent role in most processes cells lacking active such as oocytes in the cell and is critical for maintaining homeo- and reticulocytes, translational control is often stasis in the cell and the organism. The synthesis the only mechanism to regulate the synthesis rate of a protein in general is proportional to the of . Furthermore, protein synthesis ac- concentration and translational efficiency of its counts for a large proportion of the energy bud- mRNA. Translational control governs the effi- get of acell, especiallyone that is rapidly growing ciency of mRNAs and thus plays an important or biosynthetically active, and therefore requires role in modulating the expression of many tight regulation. Because protein synthesis is in- that respond to endogenous or exogenous sig- timately integrated with cell metabolism, aber- nals such as nutrient supply,hormones,or stress. rations in its regulation contribute to a number Because the vast majority of eukaryotic mRNAs of disease states. It is therefore apparent that a have quite long half- (.2 h) (Raghavan et detailed knowledge of the mechanisms that con- al. 2002), rapid regulation of the cellular levels of tribute to translational control is essential in un- the proteins they encode must be achieved by derstanding cell homeostasis and disease.

Editors: John W.B. Hershey, Nahum Sonenberg, and Michael B. Mathews Additional Perspectives on Protein Synthesis and Translational Control available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011528 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011528

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J.W.B. Hershey et al.

PROTEIN SYNTHESIS PATHWAY the initiation codon, usually AUG. Although formation of the 30S initiation complex is pro- Protein synthesis is a highly conserved process moted by three initiation factors, identification that links amino acids together on of the initiation site in the mRNA is based pri- based on the sequence of an mRNA template. marily on RNA–RNA interactions. The large To appreciate the complex pathway ribosomal subunit (50S) then binds to form a in human cells, it is useful first to consider pro- 70S initiation complex, which contains the for- tein synthesis in bacteria. The bacterial pathway myl-methionyl-tRNA in the ribosomal P-site is coupled to transcription of the DNA into and which is prepared to enter the elongation mRNA, madepossible because nonuclear mem- phase. Elongation involves three steps: the bind- braneseparatestheseprocesses.Itcomprisesfour ing of an aminoacyl-tRNA whose anticodon is phases: initiation, elongation, termination, and complementary to the mRNA codon in the ri- recycling (Fig. 1). The initiation phase involves bosomal A-site; formation of a peptide bond by thebindingofthesmallribosomal subunit (30S) transfer of the amino acid or peptide attached to to an unstructured region in the mRNA (the the tRNA in the P-site to the aminoacyl-tRNA in Shine-Dalgarno region) that is complementary theA-site;andtranslocationofthenewly formed to a portion of the 16S rRNA, and is stabilized peptidyl-tRNA from the A-site to the P-site, to- through an interaction between the - gether with the mRNA. These reactions are pro- bound initiator formyl-methionyl-tRNA and moted by a number of elongation factors and by

fMet fMet GTP

30S AUG mRNA

Initiation

50S GDP + Pi Recycling aa fMet fMet aa GTP GDP + Pi

AUG AUG Binding EPA mRNA GDP + Pi

Elongation GTP Peptidyl cycle transferase

Termination Translocation

AUG AUG EPAProtein EPA GDP + Pi GTP EPA

Figure 1. Pathway of protein synthesis in bacteria. The simplified cartoon shows the four phases of protein synthesis and how the ribosomes, tRNAs, mRNA, and GTP interact. Not shown are the initiation, elongation, and termination factors that promote the reactions. Following initiation, each turn of the elongation cycle results in the addition of another amino acid (gray pentagon) to the growing peptide chain (not shown). Termination occurs when a termination codon (UAA, UAG, UGA) appears in the ribosomal A-site and involves hydrolysis of the peptidy-tRNA in the P-site. (Figure constructed by Nancy Villa, University of California, Davis.)

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Principles of Translational Control

the ribosome itself, with rRNA playing a partic- MECHANISM OF EUKARYOTIC INITIATION ularly notable part. When a termination codon (UAA, UAG, UGA) enters the A-site, termina- To elucidate translational control mechanisms, tion factors bind to the ribosome and promote it is essential to define the detailed molecular the hydrolysis of the peptidyl-tRNA. Ribosomes mechanism of protein synthesis. The major ini- are then recycled through interactions with a tiation pathway, scanning, involves binding of a 0 number of protein factors to generate ribosomal 40S–Met-tRNAi complex to the 5 -terminus subunits capable of undergoing another round of an m7G-capped mRNA, followed by down- of protein synthesis. Detailed descriptions of stream scanning along the mRNA until an the bacterial pathway are found in a number of AUG (or near-cognate) initiation codon is rec- reviews (Laursen et al. 2005; Noller 2007). ognized. The 60S ribosomal subunit then joins Protein synthesis in higher cells shares many the 40S initiation complex to form an 80S ini- similarities with that in bacteria. The genetic tiation complex capable of entry into the elon- code is identical and the aminoacyl-tRNAs and gation phase. These reactions are promoted by their synthetases are very similar, but eukaryotic twelve or more initiation factors comprising ribosomal subunits, named 40S and 60S, are over 25 proteins (see Hinnebusch and Lorsch larger and richer in protein, as illustrated by 2012). Although much has been learned about recent high-resolution structures (see Wilson how mammalian cells initiate protein synthesis, and Cate 2012). Whereas the elongation phase a number of gaps and uncertainties remain. is strongly conserved, the initiation and termi- For example, identification of initiation factors nation/recycling phases differ substantially. A has been based on their stimulation of in vitro conspicuous feature of eukaryotic protein syn- initiation assays constructed with purified com- thesis is the fact that mRNAs are translated in ponents, and verified by genetic methods. How- the cytoplasm, making translation uncoupled ever, the recent discoveries of new proteins ap- from transcription. Mature eukaryotic mRNAs parently involved in the pathway (e.g., DHX29 possess a m7G-cap at their 50-terminus and, in [Parsyan et al. 2009] and DDX3 [Lai et al. most cases, a poly (A) tail at their 30-terminus. 2008]) suggest that all relevant initiation factors They are generally monocistronic, unlike most may not have been identified. In addition, the bacterial mRNAs, and the pathway and mecha- relevance of some identified factors is uncer- nism for the formation of 40S and 80S initiation tain. For example, eIF2A promotes the binding complexes differ substantially from those in bac- of Met-tRNAi to 40S ribosomal subunits, but its teria. For example, a large number of initiation role in translation initiation is not well estab- factors (at least 12) promote the binding of the lished (Komar et al. 2005; Ventosoet al. 2006). A mRNA and initiator methionyl-tRNAi (Met- newly identified factor, eIF2D, promotes tRNA tRNAi)—which is not formylated—to the 40S binding into the ribosomal P-site in the absence ribosomal subunit. Therefore 40S initiation of GTP,but its mechanism of action and role in complex formation involves numerous pro- initiation have not been defined (Dmitriev et al. tein–RNA and protein–protein interactions, in 2010). eIF5A promotes protein synthesis, but contrast to what occurs in bacteria. Given the whether it is involved in the initiation or elon- preeminence of the initiation phase in the reg- gation phase (Saini et al. 2009), or possibly just ulation of protein synthesis, we develop the in formation of the first peptide bond, is con- mechanism of eukaryotic initiation in consid- troversial (reviewed in Henderson and Hershey erable detail in the following section. Termina- 2011). eIF6 was first identified as an antiribo- tion and recycling resemble the reactions in pro- some association factor but its role in initiation karyotes, except that different sets of proteins was then questioned (Si and Maitra 1999); how- promote these phases. Eukaryotic initiation ever, recent structural studies show clearly how pathways are outlined in Figure 2; detailed de- binding to the nascent premature 60S subunit scriptions of the molecular mechanisms are prevents junction with the 40S initiation com- found in Hinnebusch and Lorsch (2012). plex (Klinge et al. 2011).

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J.W.B. Hershey et al.

Cap dependent IRES dependent

AUG 40S

ATP GTP Helicase Met ADP + Pi AUG

AUG

EPA

AUG

ATP AUG Scanning ADP + Pi

AUG

Initiation codon recognition GDP + Pi

AUG

60S GTP Subunit joining GDP + Pi

AUG

Figure 2. Pathway of eukaryotic initiation. The simplified cartoon shows two types of initiation mechanisms 7 (m G-cap-dependent scanning and IRES-dependent internal), and how the ribosomes, methionyl-tRNAi, mRNA, and ATP/GTP interact. Not shown are the initiation factors or the possibility that scanning follows IRES-directed binding of the 40S ribosomal subunit during internal initiation. (Figure constructed by Nancy Villa, University of California, Davis.)

Despite its centrality, aspects of the scan- from stoichiometry in the levels of some of ning mechanism are not yet well elucidated. the factors? Ribosome profiling methods detect eIF4A is a well-established RNA helicase that initiation at numerous sites in a large number functions while tethered to the cap-binding of mRNAs, some at non-AUG codons (Ingolia complex. However, does it continue to unwind et al. 2011), but how such initiation events are RNA following 40S ribosomal subunit recruit- regulated is unclear. Because rigorous kinetic ment to the mRNA, or do other identified hel- analyses of many of the reactions in initiation icases such as DHX29 (Parsyan et al. 2009) and have not been performed, we do not have a full DDX3 (Lai et al. 2008) provide the helicase description of their reaction rates, yet such in- function during scanning? Are there mechanis- formation is essential for detecting and under- tic clues in the unusual bidirectionality of the standing regulation during initiation. In con- helicase activity of eIF4A, and the departures trast, great progress has been made recently in

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Principles of Translational Control

elucidating the structure of eukaryotic ribo- through the action of trans-acting proteins (see somes (see Ben-Shem et al. 2011; Klinge et al. Gebauer et al. 2012) or (see Roux 2011; Rabl et al. 2011; Wilson and Cate 2012), and Topisirovic 2012) binding to cis-elements in although atomic resolution structures of initia- the mRNA. Some mRNAs are capable of escap- tion complexes are still lacking. ing the effects of global activation or inhibition. Besides the scanning pathway, a sizable Therefore, the response caused by a given mech- number of cellular mRNAs—generally estimat- anism may be complex in terms of the mRNAs ed as 5%–10%—may use a different way to re- affected. Methods that address this latter issue cruit the ribosome. Direct binding of the 40S are ribosome profiling (Ingolia et al. 2009) in- ribosomal subunit to an internal region of the volving high-throughput deep sequencing of mRNA, called the internal ribosome entry site ribosome-protected mRNA sequences, or DNA (IRES), bypasses the necessary recognition of microarray technology, involving identification the m7G cap (Fig. 2). IRES-mediated initiation of mRNAs in size-fractionated polysomes (see is often used for the translation of viral mRNAs, Larsson et al. 2012). Such analyses of changes in and is reported for some cellular mRNAs as well ribosome profiles caused by a difference in (see Jackson 2012 foracritical analysis of cellular physiological state enable identification of the mRNAs containing IRESs). Still other initiation mRNAs that are most affected. The polysome pathways have been described, involving shunt- profiling method is particularly powerful, as it ing (Yueh and Schneider 2000; Pooggin et al. determines where ribosomes are positioned on 2006), tethering (Martin et al. 2011), translation essentially all cellular mRNAs at a specific point enhancers (Vivinus et al. 2001), the TISU ele- in time, thereby shedding light on the phase of ment that frequently functions with mRNAs protein synthesis that changes. possessing very short 50-UTRs (Elfakess et al. Another important feature of translational 2011), and a poly-adenylate leader in the 50- control is that a change in physiological state can UTR that appears to function in the absence of activate multiple regulatory mechanisms that a number of the canonically required initiation affect the rate of protein synthesis. Such redun- factors (Shirokikh and Spirin 2008). Although dancy complicates mechanistic studies, because we already possess much sophisticated knowl- interfering with one mechanism does not nec- edge of how these initiation pathways proceed, essarily alter the overall extent of inhibition thereremains much tobelearned thatis essential or activation. A further complication is that a for a full understanding of translational control. given mechanism may itself cause only a minor change in protein synthesis rate. However, when multiple weak mechanisms act on the system FEATURES OF TRANSLATIONAL CONTROL together, significant translational control can Regulation of protein synthesis may occur at result. Mechanisms that are modest in their ac- different steps of the pathway, with the initia- tion are especially difficult to elucidate, as their tion phase being the most common target. effects sometimes only slightly alter a specific Which phase of protein synthesis is affected is reaction rate. To detect and assess the impor- often identified by determining polysome pro- tance of such mechanisms, sophisticated and files (Merrick and Hensold 2000) and ribosome highly accurate kinetic analyses are required, transit times (Fan and Penman 1970; Palmiter and are increasingly being pursued. 1972). One of the salient features of translation- al control involves the number of mRNAs affect- REGULATORY MECHANISMS ed. A given mechanism might affect the trans- lation of a single mRNA, a subset of mRNAs, or Recruitment of the mRNA to the 40S ribosomal most mRNAs. Global regulation often is based subunit is thought to be the rate-limiting step of on the activation or inhibition of one or more initiation, and is often modulated. The binding components of the translational machinery, of methionyl-tRNAi also is frequently regulated, whereas specific regulation frequently occurs and subsequent steps such as scanning and

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initiator codon recognition may be affected as mRNA deadenylation may resolve the contro- well. How are these reactions regulated? The versy of which effect is dominant (Fabian et al. cellular levels of the canonical initiation factors 2009). differ in various cell or tissue types, thereby af- Trans-acting proteins affect initiation rates fecting initiation rates. Modulating the activi- by binding to specific mRNAs and interfering ties of the initiation factors by with various steps of the pathway (see Gebauer is often used to regulate global rates of protein et al. 2012). Such proteins frequently recognize synthesis. The best-studied examples are phos- a binding site in the 30-UTR, yet affect events phorylation of eIF2a, which results in an inhi- occurring near the 50-m7G cap. These regulatory bition of Met-tRNAi binding to ribosomes (see mechanisms often function during early devel- Hinnebusch and Lorsch 2012; Pavitt and Ron opment (see Gebauer et al 2012; Lasko 2012) via 2012), and phosphorylation of 4E-BPs (seques- protein-mediated crosstalk between the two tors of the cap-binding protein, eIF4E), which ends of the mRNAs. Indeed, active mRNAs are relieves translational repression caused by de- thought to be circularized through an interac- creased mRNA recognition and binding to ri- tion between the poly (A)-binding protein bosomes (see Hinnebusch and Lorsch 2012; (PABP) and eIF4G, which is a component of the Roux and Topisirovic 2012). Numerous other m7G-cap-binding complex (Wells et al. 1998). initiation factors are phosphorylated, often as Some mRNAs, for example the histone mRNAs targets of signal transduction pathways, as are that lack a poly (A) tail, are circularized through ribosomes and the elongation factor eEF2, but specialized proteins that bind near the 30-termi- how such events regulate protein synthesis is not nus of the mRNA and react with the cap-bind- yet well established. Besides phosphorylation, ing protein complex (Cakmakci et al. 2008). posttranslational modifications such as methyl- However, mutant yeast lacking the PABP-eIF4G ation, ubiquitination, and glycosylation, may interaction show normal translation rates (Park affect protein synthesis, but these have not been et al. 2011), which suggests that circularization studied extensively. One can anticipate that does not invariably promote initiation, at least mass spectrometric methods will identify new not in yeast. Another possibility, not yet estab- modifications of importance in the near future. lished, is that circularization enhances the abil- mRNA levels appear not to be rate-limiting ity of a terminating ribosome to reinitiate on the for global protein synthesis in many cells, as a same mRNA, perhaps by a mechanism that dif- substantial number of mRNAs are found as un- fers from the canonical scanning mechanism. translated,freemRNPsratherthaninactivepoly- During analyses of the generation of polysomes somes. However, mRNAs also can be seques- in vitro, the rate of addition of a new ribosome tered in stress granules or P-bodies (see Decker to a polysome was slower than the ribosome and Parker 2012) or localized in specific regions transit time, yet polysome size increased, sug- of a cell’s cytoplasm (see Chao et al. 2012; Lasko gesting that ribosomes already present on a 2012), indicating that mRNA accessibility can polysome reinitiate more efficiently on the influence the efficiency of translation. same mRNA than new ribosomes initiate (Nel- Regulation of translation through the action son and Winkler 1987). of microRNAs is an exciting new area of study. Although less commonly reported, the elon- MicroRNAs can stimulate the degradation of gation and termination phases (see Dever and mRNAs or affect protein synthesis directly (see Green 2012) also are targets of translational con- Braun et al. 2012). The mode of regulation is trol. The rate of elongation is thought to be max- mRNA-specific, although a single microRNA imal under most conditions (Ingolia et al. 2011), may affect a number of different mRNAs. Pre- but can be inhibited by specific mechanisms. cise mechanisms whereby the microRNAs affect Whether such inhibition affects the elongation protein synthesis are yet to be elucidated. Recent rates of all mRNAs equally is not well estab- in vitro experiments detecting early microRNA- lished. Only when elongation is slowed suffi- based inhibition of protein synthesis prior to ciently, such that initiation is no longer rate-

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Principles of Translational Control

limiting, is the rate of protein synthesis affected. FUTURE PROSPECTS The occurrence of rare codons or strong second- ary structure in the coding region of a mRNA is New discoveries of the involvement of transla- thought to slow the rate of elongation. Some tional control in cell metabolism, proliferation mRNAs can thereby be induced to undergo a and disease are being reported constantly. The shift in reading frame at a specific region, gen- ribosome profiling method has already identi- erating a protein whose sequence and length dif- fied unexpected changes in the translation of fer from the unshifted one. For proteins that are numerous specific mRNAs and can be expected to be inserted into the endoplasmic reticulum, to generate a vast amount of new data. Handling their elongation is paused by the signal recogni- the plethora of information requires new and tion particle, enabling the amino terminus of sophisticated bioinformatic methods that are the nascent protein to dock onto the endoplas- rapidly beingdeveloped andrefined(see Larsson mic reticulum, after which elongation resumes et al. 2012). A challenge is presented by the pro- (see Benham 2012). The rate of elongation af- liferation of gene products, including alterna- fects the folding of proteins (see Cabrita et al. tively processed mRNAs and protein isoforms, 2010); if elongation is too fast, e.g., when recom- produced in higher cells. This diversification in- binant eukaryotic proteins are synthesized in troduces additional levels of complexity that bacteria, many proteins fail to fold properly un- need to be accommodated in these analyses. less the overall rate is reduced (Siller et al. 2010). Such high-throughput approaches do not gen- Alternatively, slowing the elongation rate at spe- erally elucidate details of the molecular mecha- cific regions of the mRNA may enhance proper nisms involved, however. Tounderstand the ob- folding (Zhang et al. 2009), further demonstrat- served changes in mRNA translation, many of ing the link between rates orelongation and pro- them rather modest in extent, it is necessary to tein folding. Furthermore, the folding of the have a precise knowledge of the mechanism of nascent protein as it emerges from the large ri- protein synthesis. bosomal subunit can affect the elongation rate, What are the major challenges for under- either positively or negatively (see Cabrita et al. standing translational control mechanisms? We 2010). already have a fairly detailed description of the The termination phase also may be regulated process of protein synthesis during the initia- (reviewed in Dinman and Berry 2007). Under tion, elongation, termination, and recycling most circumstances, termination is not rate- phases. With the recent ability to obtain crystals limiting for protein synthesis, because ribo- of eukaryotic ribosomes (Ben-Shem et al. 2011; somes are not found stacked up at the ends Klinge et al. 2011; Rabl et al. 2011), we can an- of mRNAs. However, termination can be sup- ticipate atomic level structures of ribosome pressed, enabling either frame-shifting or read- complexes that are essential for describing how through to occur, thereby extending the nascent peptide bonds are formed and how the various protein at its carboxyl terminus. The UGA stop factors interact on the surface of the ribosome to codon can be reprogrammed to enable the in- promote initiation, elongation, and termina- sertion of a seleno-cysteine residue rather than tion. However, crystals of 40S and 80S initiation to terminate synthesis. Incorporated into pro- complexes have eluded researchers, and even teins by the translational process itself, seleno- cryo-electron microscopic approaches have not cysteine has been called the “21st amino acid,” yet yielded sufficiently precise structures of these and it is now followed by the 22nd—pyrroly- important intermediates. Another area lacking sine, encoded by a UAG codon in some meth- structural information at high resolution per- anogenic archaea and bacteria (Atkins and Ges- tains to mRNAs. Although computer programs teland 2002). Such “amendments” to the can predict structural motifs in RNA (Cruz and elongation and termination steps are influenced Westhof 2011), the actual 3-dimensional struc- by the sequence context of the codon, or by tures, especially those of the 50-UTR, are only other features of the mRNA. now beginning to be determined (Steen et al.

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2011). Such detailed structures of mRNAs and more and more examples of regulation at the their native mRNP complexes are eagerly await- level of protein synthesis will be discovered. A ed, as they surely are important for mRNA bind- number of promising areas of research are fea- ing, scanning and initiator codon recognition tured in this volume. We anticipate that regula- during initiation. mRNA structures also affect tion by microRNAs will prove to be important the elongation and termination rates, thereby for the translation for most mRNAs (Braun affecting protein folding and the regulation of et al. 2012). How does the secretion or cotrans- frameshifting. So high-resolution mRNA struc- lational folding of nascent proteins affect their tural information, especially pertaining to the synthesis (Cabrita et al. 2010; Benham 2012)? initiation phase, is needed. Other areas in which translational control al- Another area in which our knowledge is ready is firmly established are described in lit- limited pertains to the kinetics of the various erature dealing with cell development (Lasko reactions, interactions and conformational 2012), cancer (Ruggero 2012), synaptic plastic- changes involved in protein synthesis. The elon- ity and memory (Darnell and Richter 2012), gation phase is relatively well characterized, es- and viruses (Walsh et al. 2012). As translational pecially for prokaryotes, but there are numerous control mechanisms are better understood and initiation steps that are yet to be studied in de- as high throughput methods identify when such tail. Insights into the kinetics of initiation com- regulation occurs, we can confidently anticipate plex formation have been gained from studies that we will learn of additional areas of cellular primarily performed with yeast components metabolism that are modulated through pro- (reviewed in Lorsch and Dever 2010 and Hin- tein synthesis. Indeed, it is becoming clear that nebusch and Lorsch 2012), yet much is yet to be translational control and transcriptional con- learned. Do initiation factors form subcom- trol are comparably important in regulating plexes off the ribosome, or do they first bind gene expression. to the 40S subunits, and if so, in what order? The relevance and importance of protein Which proteins mediate the binding of Met- synthesis in disease and medicine is increasingly tRNAi to 40S ribosomes, and how is that rate recognized and appreciated. The dysregulation affected by other initiation factors? What is the of protein synthesis in a specific disease pro- rate of ribosome scanning of the 50-UTR, and is vides a target for therapeutic intervention (see this rate affected by changes in the activities of Malina et al. 2012). As our knowledge of the associated initiation factors, e.g., those involved structures and detailed mechanisms of protein in RNA helicase activity? Why do ribosomes synthesis improve, this information can be ap- appear to idle at the initiator AUG codon? That plied to enable more rational drug design. is, what limits their rapid progression into the Therefore, research in the area of translational elongation phase? Most kinetic analyses average control will contribute to a better understand- the effects of many molecules over time. The ing of many disease states and to the develop- application of single molecule studies to the ment of novel therapeutic agents. kinetics of protein synthesis (see Petrov et al. 2012) likely will generate new views of how such reactions proceed. Additional work em- REFERENCES ploying both single molecule and standard ki- Reference is also in this collection. netic methods are needed to properly recognize and evaluate many of the translational control Atkins J, Gesteland R. 2002. The 22nd amino acid. Science 296: 1409–1410. mechanisms that operate at the initiation phase, Benham AM. 2012. Protein secretion and the endoplasmic especially those mechanisms that only margin- reticulum. Cold Spring Harb Perspect Biol doi: 10.1101/ ally affect reaction rates. cshperspect.a012872. Complementing our constantly increasing Ben-Shem A, de Loubresse N, Melnikov S, Jenner L, Yusupova G, Yusupov M. 2011. The structure of the eu- understanding of the molecular mechanisms karyotic ribosome at 3.0 A˚ resolution. Science 334: of translational control is the expectation that 1524–1529.

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Principles of Translational Control: An Overview

John W.B. Hershey, Nahum Sonenberg and Michael B. Mathews

Cold Spring Harb Perspect Biol 2012; doi: 10.1101/cshperspect.a011528

Subject Collection Protein Synthesis and Translational Control

Tinkering with Translation: Protein Synthesis in Toward a Genome-Wide Landscape of Virus-Infected Cells Translational Control Derek Walsh, Michael B. Mathews and Ian Mohr Ola Larsson, Bin Tian and Nahum Sonenberg Translational Control in Cancer Etiology The Current Status of Vertebrate Cellular mRNA Davide Ruggero IRESs Richard J. Jackson A Molecular Link between miRISCs and Principles of Translational Control: An Overview Deadenylases Provides New Insight into the John W.B. Hershey, Nahum Sonenberg and Mechanism of Gene Silencing by MicroRNAs Michael B. Mathews Joerg E. Braun, Eric Huntzinger and Elisa Izaurralde Imaging Translation in Single Cells Using Regulation of mRNA Translation by Signaling Fluorescent Microscopy Pathways Jeffrey A. Chao, Young J. Yoon and Robert H. Philippe P. Roux and Ivan Topisirovic Singer mRNA Localization and Translational Control in The Mechanism of Eukaryotic Translation Drosophila Oogenesis Initiation: New Insights and Challenges Paul Lasko Alan G. Hinnebusch and Jon R. Lorsch P-Bodies and Stress Granules: Possible Roles in Single-Molecule Analysis of Translational the Control of Translation and mRNA Degradation Dynamics Carolyn J. Decker and Roy Parker Alexey Petrov, Jin Chen, Seán O'Leary, et al. Protein Secretion and the Endoplasmic Reticulum Cytoplasmic RNA-Binding Proteins and the Adam M. Benham Control of Complex Brain Function Jennifer C. Darnell and Joel D. Richter From Cis-Regulatory Elements to Complex RNPs The Elongation, Termination, and Recycling and Back Phases of Translation in Eukaryotes Fátima Gebauer, Thomas Preiss and Matthias W. Thomas E. Dever and Rachel Green Hentze

For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/

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