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Cold Spring Harbor Perspectives in Biology

John W B Hershey, Nahum Sonenberg, Michael B Mathews
Protein synthesis involves a complex machinery comprising numerous proteins and RNAs joined by noncovalent interactions. Its function is to link long chains of amino acids into proteins with precise sequences as encoded by the genome. Regulation of protein synthesis, called translational control, occurs both at a global level and at specific messenger RNAs (mRNAs). To understand how translation is regulated, knowledge of the molecular structures and kinetic interactions of its components is needed. This review focuses on the targets of translational control and the mechanisms employed...
June 29, 2018: Cold Spring Harbor Perspectives in Biology
Thomas F Duchaine, Marc R Fabian
MicroRNAs (miRNAs) posttranscriptionally regulate gene expression by repressing protein synthesis and exert a broad influence over development, physiology, adaptation, and disease. Over the past two decades, great strides have been made toward elucidating how miRNAs go about shutting down messenger RNA (mRNA) translation and promoting mRNA decay.
June 29, 2018: Cold Spring Harbor Perspectives in Biology
Nathaniel Robichaud, Nahum Sonenberg, Davide Ruggero, Robert J Schneider
The translation of messenger RNAs (mRNAs) into proteins is a key event in the regulation of gene expression. This is especially true in the cancer setting, as many oncogenes and transforming events are regulated at this level. Cancer-promoting factors that are translationally regulated include cyclins, antiapoptotic factors, proangiogenic factors, regulators of cell metabolism, prometastatic factors, immune modulators, and proteins involved in DNA repair. This review discusses the diverse means by which cancer cells deregulate and reprogram translation, and the resulting oncogenic impacts, providing insights into the complexity of translational control in cancer and its targeting for cancer therapy...
June 29, 2018: Cold Spring Harbor Perspectives in Biology
Masaaki Sokabe, Christopher S Fraser
The eukaryotic translation pathway has been studied for more than four decades, but the molecular mechanisms that regulate each stage of the pathway are not completely defined. This is in part because we have very little understanding of the kinetic framework for the assembly and disassembly of pathway intermediates. Steps of the pathway are thought to occur in the subsecond to second time frame, but most assays to monitor these events require minutes to hours to complete. Understanding translational control in sufficient detail will therefore require the development of assays that can precisely monitor the kinetics of the translation pathway in real time...
June 29, 2018: Cold Spring Harbor Perspectives in Biology
Christopher G Proud
Protein synthesis, including the translation of specific messenger RNAs (mRNAs), is regulated by extracellular stimuli such as hormones and by the levels of certain nutrients within cells. This control involves several well-understood signaling pathways and protein kinases, which regulate the phosphorylation of proteins that control the translational machinery. These pathways include the mechanistic target of rapamycin complex 1 (mTORC1), its downstream effectors, and the mitogen-activated protein (MAP) kinase (extracellular ligand-regulated kinase [ERK]) signaling pathway...
June 29, 2018: Cold Spring Harbor Perspectives in Biology
Thaddaeus Kwan, Sunnie R Thompson
The vast majority of eukaryotic messenger RNAs (mRNAs) initiate translation through a canonical, cap-dependent mechanism requiring a free 5' end and 5' cap and several initiation factors to form a translationally active ribosome. Stresses such as hypoxia, apoptosis, starvation, and viral infection down-regulate cap-dependent translation during which alternative mechanisms of translation initiation prevail to express proteins required to cope with the stress, or to produce viral proteins. The diversity of noncanonical initiation mechanisms encompasses a broad range of strategies and cellular cofactors...
June 29, 2018: Cold Spring Harbor Perspectives in Biology
Amy Jobe, Zheng Liu, Cristina Gutierrez-Vargas, Joachim Frank
In the past 4 years, because of the advent of new cameras, many ribosome structures have been solved by cryoelectron microscopy (cryo-EM) at high, often near-atomic resolution, bringing new mechanistic insights into the processes of translation initiation, peptide elongation, termination, and recycling. Thus, cryo-EM has joined X-ray crystallography as a powerful technique in structural studies of translation. The significance of this new development is that structures of ribosomes in complex with their functional binding partners can now be determined to high resolution in multiple states as they perform their work...
June 14, 2018: Cold Spring Harbor Perspectives in Biology
Tao Zu, Amrutha Pattamatta, Laura P W Ranum
More than 40 different neurological diseases are caused by microsatellite repeat expansions that locate within translated or untranslated gene regions, including 5' and 3' untranslated regions (UTRs), introns, and protein-coding regions. Expansion mutations are transcribed bidirectionally and have been shown to give rise to proteins, which are synthesized from three reading frames in the absence of an AUG initiation codon through a novel process called repeat-associated non-ATG (RAN) translation. RAN proteins, which were first described in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1), have now been reported in a growing list of microsatellite expansion diseases...
June 11, 2018: Cold Spring Harbor Perspectives in Biology
Arjun Prabhakar, Elisabetta Viani Puglisi, Joseph D Puglisi
Single-molecule fluorescence methods have illuminated the dynamics of the translational machinery. Structural and bulk biochemical experiments have provided detailed atomic and global mechanistic views of translation, respectively. Single-molecule studies of translation have bridged these views by temporally connecting the conformational and compositional states defined from structural data within the mechanistic framework of translation produced from biochemical studies. Here, we discuss the context for applying different single-molecule fluorescence experiments, and present recent applications to studying prokaryotic and eukaryotic translation...
June 11, 2018: Cold Spring Harbor Perspectives in Biology
Noam Stern-Ginossar, Sunnie R Thompson, Michael B Mathews, Ian Mohr
As obligate intracellular parasites, virus reproduction requires host cell functions. Despite variations in genome size and configuration, nucleic acid composition, and their repertoire of encoded functions, all viruses remain unconditionally dependent on the protein synthesis machinery resident within their cellular hosts to translate viral messenger RNAs (mRNAs). A complex signaling network responsive to physiological stress, including infection, regulates host translation factors and ribosome availability...
June 11, 2018: Cold Spring Harbor Perspectives in Biology
Evangelos D Karousis, Oliver Mühlemann
Nonsense-mediated mRNA decay (NMD) is arguably the best-studied eukaryotic messenger RNA (mRNA) surveillance pathway, yet fundamental questions concerning the molecular mechanism of target RNA selection remain unsolved. Besides degrading defective mRNAs harboring premature termination codons (PTCs), NMD also targets many mRNAs encoding functional full-length proteins. Thus, NMD impacts on a cell's transcriptome and is implicated in a range of biological processes that affect a broad spectrum of cellular homeostasis...
June 11, 2018: Cold Spring Harbor Perspectives in Biology
Ronald R Breaker
A growing collection of bacterial riboswitch classes is being discovered that sense central metabolites, coenzymes, and signaling molecules. Included among the various mechanisms of gene regulation exploited by these RNA regulatory elements are several that modulate messenger RNA (mRNA) translation. In this review, the mechanisms of riboswitch-mediated translation control are summarized to highlight both their diversity and potential ancient origins. These mechanisms include ligand-gated presentation or occlusion of ribosome-binding sites, control of alternative splicing of mRNAs, and the regulation of mRNA stability...
May 29, 2018: Cold Spring Harbor Perspectives in Biology
Christopher U T Hellen
Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide. The post-termination complex is then disassembled, enabling its constituents to participate in further rounds of translation. Ribosome recycling involves splitting of the 80S ribosome by the ATP-binding cassette protein ABCE1 to release the 60S subunit...
May 7, 2018: Cold Spring Harbor Perspectives in Biology
William C Merrick, Graham D Pavitt
This review summarizes our current understanding of the major pathway for the initiation phase of protein synthesis in eukaryotic cells, with a focus on recent advances. We describe the major scanning or messenger RNA (mRNA) m7 G cap-dependent mechanism, which is a highly coordinated and stepwise regulated process that requires the combined action of at least 12 distinct translation factors with initiator transfer RNA (tRNA), ribosomes, and mRNAs. We limit our review to studies involving either mammalian or budding yeast cells and factors, as these represent the two best-studied experimental systems, and only include a reference to other organisms where particular insight has been gained...
May 7, 2018: Cold Spring Harbor Perspectives in Biology
Salim Mamajiwalla
Patent law is an area that many people move into after obtaining a PhD in biomedical science. Close to the cutting edge of research, patent agents draft detailed descriptions of new biotechnology inventions required for patent applications and engage with patent offices during the review process known as patent prosecution. Jobs are also available as patent examiners who examine these patent applications, and it is common for individuals to move between the two jobs. A law firm is generally the best place to train as a patent agent, but biotech companies and tech-transfer offices can provide an alternative route...
July 2, 2018: Cold Spring Harbor Perspectives in Biology
Chun Kit Kwok, Giovanni Marsico, Shankar Balasubramanian
SUMMARYRNA G-quadruplex (rG4) secondary structures are proposed to play key roles in fundamental biological processes that include the modulation of transcriptional, co-transcriptional, and posttranscriptional events. Recent methodological developments that include predictive algorithms and structure-based sequencing have enabled the detection and mapping of rG4 structures on a transcriptome-wide scale at high sensitivity and resolution. The data generated by these studies provide valuable insights into the potentially diverse roles of rG4s in biology and open up a number of mechanistic hypotheses...
July 2, 2018: Cold Spring Harbor Perspectives in Biology
Thomas D Pollard, Robert D Goldman
SUMMARYOrganisms in the three domains of life depend on protein polymers to form a cytoskeleton that helps to establish their shapes, maintain their mechanical integrity, divide, and, in many cases, move. Eukaryotes have the most complex cytoskeletons, comprising three cytoskeletal polymers-actin filaments, intermediate filaments, and microtubules-acted on by three families of motor proteins (myosin, kinesin, and dynein). Prokaryotes have polymers of proteins homologous to actin and tubulin but no motors, and a few bacteria have a protein related to intermediate filament proteins...
July 2, 2018: Cold Spring Harbor Perspectives in Biology
Holly V Goodson, Erin M Jonasson
SUMMARYMicrotubules act as "railways" for motor-driven intracellular transport, interact with accessory proteins to assemble into larger structures such as the mitotic spindle, and provide an organizational framework to the rest of the cell. Key to these functions is the fact that microtubules are "dynamic." As with actin, the polymer dynamics are driven by nucleotide hydrolysis and influenced by a host of specialized regulatory proteins, including microtubule-associated proteins. However, microtubule turnover involves a surprising behavior-termed dynamic instability-in which individual polymers switch stochastically between growth and depolymerization...
June 1, 2018: Cold Spring Harbor Perspectives in Biology
Jennifer Chu, Jerry Pelletier
The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of translation...
June 1, 2018: Cold Spring Harbor Perspectives in Biology
Carla B Green
The circadian clock drives rhythms in the levels of thousands of proteins in the mammalian cell, arising in part from rhythmic transcriptional regulation of the genes that encode them. However, recent evidence has shown that posttranscriptional processes also play a major role in generating the rhythmic protein makeup and ultimately the rhythmic physiology of the cell. Regulation of steps throughout the life of the messenger RNA (mRNA), ranging from initial mRNA processing and export from the nucleus to extensive control of translation and degradation in the cytosol have been shown to be important for producing the final rhythms in protein levels critical for proper circadian rhythmicity...
June 1, 2018: Cold Spring Harbor Perspectives in Biology
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