The conserved ribosomal protein uS3 in eukaryotes has long been known as one of the essential components of the small (40S) ribosomal subunit, which is involved in the structure of the 40S mRNA entry pore, ensuring the functioning of the 40S subunit during translation initiation. Besides, uS3, being outside the ribosome, is engaged in various cellular processes related to DNA repair, NF‐kB signaling pathway and regulation of apoptosis. This review is devoted to recent data opening new horizons in understanding the (...) roles of uS3 in such processes as the assembly and maturation of 40S subunits, ensuring proper structure of 48S pre‐initiation complexes, regulation of initiation and ribosome‐based RNA quality control pathways. Besides, we summarize novel results on the participation of the protein in processes beyond translation and consider biomedical implications of previously known and recently found extra‐ribosomal functions of uS3, primarily, in oncogenesis. (shrink)

Ribosome biogenesis includes the making and processing of ribosomal RNAs, the biosynthesis of ribosomal proteins from their mRNAs in the cytosol and their transport to the nucleolus to assemble pre‐ribosomal particles. Several stresses including cellular senescence reduce nucleolar rRNA synthesis and maturation increasing the availability of ribosome‐free ribosomal proteins. Several ribosomal proteins can activate the p53 tumor suppressor pathway but cells without p53 can still arrest their proliferation in response to an imbalance between ribosomal proteins and mature rRNA production. Recent (...) results on senescence‐associated ribogenesis defects (SARD) show that the ribosomal protein S14 (RPS14 or uS11) can act as a CDK4/6 inhibitor linking ribosome biogenesis defects to the main engine of cell cycle progression. This work offers new insights into the regulation of the cell cycle and suggests novel avenues to design anticancer drugs. (shrink)

Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native three‐dimensional structure. Modular assembly of individual RNA domains through interactions with ribosomal proteins and a myriad of assembly factors permit efficient disentanglement of the error‐prone RNA folding process. Following these dynamic events, long‐range tertiary interactions are orchestrated to compact rRNA. A combination of genetic, biochemical, and structural studies is now providing clues into how a (...) nascent rRNA is transformed into a functional ribosome with high precision. With this essay, we aim to draw attention to the poorly understood process of establishing correct RNA tertiary contacts during ribosome formation. (shrink)

Dormancy or hibernation is a non‐proliferative state of cells with low metabolic activity and gene expression. Dormant cells sequester ribosomes in a translationally inactive state, called dormant/hibernating ribosomes. These dormant ribosomes are important for the preservation of ribosomes and translation shut‐off. While recent studies attempted to elucidate their modes of formation, the regulation and roles of the diverse dormant ribosomal populations are still largely understudied. The mechanistic details of the formation of dormant ribosomes in stress (...) and especially their disassembly during recovery remain elusive. In this review, we discuss the roles of dormant ribosomes and their potential regulatory mechanisms. Furthermore, we highlight the paradigms that need to be answered in the field of ribosomal dormancy. (shrink)

It was first suggested that the ribosome is associated with protein synthesis in the 1950s. Initially, its components were revealed as surface‐accessible proteins and as molecules of RNA apparently providing a scaffold for subunit shape. Attributing function to the proteins proved difficult, although bacterial protein L11 proved essential for binding one of the decoding protein release factors (RFs). With the discovery that RNA could be a catalyst, interest focussed on the rRNA that, in partnership with mRNA and tRNAs, could potentially (...) mediate the chemical reaction underlying protein synthesis. rRNA interactions and conformational changes were invoked as key elements that facilitated function. The decoding RFs, which are proteins, are exceptions to this rule because they usurp a tRNA function in mediating stop signal recognition. Cryoelectron microscopy and associated image reconstruction technology have now given dramatic snapshots of almost every step of protein synthesis, and X‐ray crystallography has revealed, at last, the subunits and monomeric ribosome in exquisite atomic detail. BioEssays 26:582–588, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Most eukaryotes possess many copies of rDNA. Organismal selection alone cannot maintain rRNA function because the effects of mutations in one rDNA are diluted by the presence of many other rDNAs. rRNA quality is maintained by processes that increase homogeneity of rRNA within, and heterogeneity among, germ cells thereby increasing the effectiveness of cellular selection on ribosomal function. A successful rDNA repeat will possess adaptations for spreading within tandem arrays by intranuclear selection. These adaptations reside in the non‐coding regions of (...) rDNA. Single‐copy genes are predicted to manage processes of intranuclear and cellular selection in the germline to maintain the quality of rRNA expressed in somatic cells of future generations. (shrink)

The levels of different classes of mitochondrially encoded transcripts are developmentally regulated in sea urchin embryos, as a result of selection between mutually exclusive synthetic pathways. I propose a simple model to explain these observations, based on a dual role for mitochondrial ribosomes and translation factors in RNA synthesis as well as in translation. This effect may be exerted either at the transcriptional or post‐transcriptional level (or both), and is potentially generalizable to mammalian mtDNA and to other systems.

Autoantibodies to three eukaryotic 60S ribosomal phosphoproteins P0, P1 and P2 have been found in the sera of 10–20% of patients with systemic lupus erythematosus (SLE). These three proteins share a common epitope contained within the carboxy terminal 22 amino acids of each protein. Because central nervous system disturbances, with major behavioural disorders, occur in a significant fraction of SLE patients, the antiribosomal autoantibodies were measured in this subset of SLE individuals to determine whether or not there was an association. (...) This antibody is present in 90% of SLE patients who were diagnosed as having psychosis, secondary to the disease. (shrink)

Applying mild methods of preparation, part of the ribosomes of rabbit reticulocytes are found in aggregates (later called polyribosomes) of up to six ribosomal units. Upon treatment with RNA-ase, they desintegrate into single ribosomes. The fast-sedimenting aggregates are found to be more active in protein synthesis in terms of incorporation of radioactive amino acids, whereas the single ribosomes are more receptive to stimulation by the artificial messenger RNA poly-U. The findings indicate that the linkage of ribosomes (...) into aggregates is due to the messenger RNA. They support a tape-reading mechanism of protein synthesis whereby growth of the peptide chain is accompanied by shifting the active site of the ribosome from one coding group of nucleotides of the messenger RNA to the next. (shrink)

Eukaryotic genes are divided into three categories according to the machineries by which they are transcribed. Ribosomal RNA genes (rDNA) are the only ones that are transcribed by RNA polymerase I and are under different control from other genes transcribed by RNA polymerase II or III. None the less, the regulation of rDNA is of prime interest in view of its close relationship to cell growth and differentiation. In this review I shall discuss the recent progress in the study of (...) transcription mechanisms of rDNA by the RNA polymerase I system. The structure of the rDNA promoter and the presence of possible upstream enhancer regions will be described. In addition, factors involved in the transcription initiation of this gene will be discussed with special reference to the formation of an initiation complex. (shrink)

Neurodegenerative syndromes present as proteinopathies – does ribosomal infidelity contribute to the protein toxicity that is the driving force for neuronal cell loss? Intracellular and extracellular protein aggregates overwhelm the clearance capacity of cells and tissues. Proteins aggregate when hydrophobic residues are exposed. Hydrophobic residues become exposed when proteins are misfolded. Protein misfolding can originate from translational errors at the ribosome. Indeed, the most error‐prone process in gene expression is translation at the ribosome. Recent evidence indicates that manipulating the ribosomal (...) accuracy impacts on the lifespan of model organisms and a reduced translational accuracy is accompanied by neurodegeneration. The first hit in aging‐associated neurodegenerative disease may be the well‐documented decline of cellular buffering capacity by aging. A second hit that impacts on the quality of protein synthesis could be the driving force for the observed loss of proteostasis in neurodegeneration. This hypothesis provides an explanation for the late onset of most neurodegenerative diseases. (shrink)

Although genome‐scale analyses have provided insights into the connection between genetic variability and complex human phenotypes, much trait variation is still not fully understood. Genetic variation within repetitive elements, such as the multi‐copy, multi‐locus ribosomal DNA (rDNA), has emerged as a potential contributor to trait variation. Whereas rDNA was long believed to be largely uniform within a species, recent studies have revealed substantial variability in the locus, both within and across individuals. This variation, which takes the form of copy number, (...) structural arrangement, and sequence differences, has been found to be associated with human phenotypes. This review summarizes what is currently known about human rDNA variation, its causes, and its association with phenotypic outcomes, highlighting the technical challenges the field faces and the solutions proposed to address them. Finally, we suggest experimental approaches that can help clarify the elusive mechanisms underlying the phenotypic consequences of rDNA variation. (shrink)

The ribosomal polypeptide tunnel exit is the site where a variety of factors interact with newly synthesized proteins to guide them through the early steps of their biogenesis. In mitochondrial ribosomes, this site has been considerably modified in the course of evolution. In contrast to all other translation systems, mitochondrial ribosomes are responsible for the synthesis of only a few hydrophobic membrane proteins that are essential subunits of the mitochondrial respiratory chain. Membrane insertion of these proteins occurs co‐translationally (...) and is connected to a sophisticated assembly process that not only includes the assembly of the different subunits but also the acquisition of redox co‐factors. Here, we describe how mitochondrial translation is organized in the context of respiratory chain assembly and speculate how alteration of the ribosomal tunnel exit might allow the establishment of a subset of specialized ribosomes that individually organize the early steps in the biogenesis of distinct mitochondrially‐encoded proteins. (shrink)

Fundamental questions in evolution concern deep divisions in the living world and vertical versus horizontal information transfer. Two contrasting views are: (i) three superkingdoms Archaea, Eubacteria, and Eukarya based on vertical inheritance of genes encoding ribosomes; versus (ii) a prokaryotic/eukaryotic dichotomy with unconstrained horizontal gene transfer (HGT) among prokaryotes. Vertical inheritance implies continuity of cytoplasmic and structural information whereas HGT transfers only DNA. By hypothesis, HGT of the translation machinery is constrained by interaction between new ribosomal gene products and (...) vertically inherited cytoplasmic structure made largely of preexisting ribosomes. Ribosomes differentially enhance the assembly of new ribosomes made from closely related genes and inhibit the assembly of products from more distal genes. This hypothesis suggests experiments for synthetic biology: the ability of synthetic genomes to “boot,” i.e., establish hereditary continuity, will be constrained by the phylogenetic closeness of the cell “body” into which genomes are placed. (shrink)

The translocation of tRNAs through the ribosome proceeds through numerous small steps in which tRNAs gradually shift their positions on the small and large ribosomal subunits. The most urgent questions are: (i) whether these intermediates are important; (ii) how the ribosomal translocase, the GTPase elongation factor G (EF‐G), promotes directed movement; and (iii) how the energy of GTP hydrolysis is coupled to movement. In the light of recent advances in biophysical and structural studies, we argue that intermediate states of translocation (...) are snapshots of dynamic fluctuations that guide the movement. In contrast to current models of stepwise translocation, kinetic evidence shows that the tRNAs move synchronously on the two ribosomal subunits in a rapid reaction orchestrated by EF‐G and GTP hydrolysis. EF‐G combines the energy regimes of a GTPase and a motor protein and facilitates tRNA movement by a combination of directed Brownian ratchet and power stroke mechanisms. (shrink)

Translation of the genetic code occurs in a cycle where ribosomes engage mRNAs, synthesize protein, and then disengage in order to repeat the process again. The final part of this process—ribosome recycling, where ribosomes dissociate from mRNAs—involves a complex molecular choreography of specific protein factors to remove the large and small subunits of the ribosome in a coordinated fashion. Errors in this process can lead to the accumulation of ribosomes at stop codons or translation of downstream open (...) reading frames (ORFs). Ribosome recycling is also critical when a ribosome stalls during the elongation phase of translation and must be rescued to allow continued translation of the mRNA. Here we discuss the molecular interactions that drive ribosome recycling, and their regulation in the cell. We also examine the consequences of inefficient recycling with regards to disease, and its functional roles in synthesis of novel peptides, regulation of gene expression, and control of mRNA‐associated proteins. Alterations in ribosome recycling efficiency have the potential to impact many cellular functions but additional work is needed to understand how this regulatory power is utilized. (shrink)

emerging field of nanotechnology. Nanotechnology gets its name from the nanometer, a distance of 10 -9 meters or roughly the diameter of a molecule, and the term refers to the technology for structuring matter with precise control at the nanometer scale, atom-by-atom or molecule-by-molecule, to form a pre-specified pattern. In other words, nanotechnology is the general ability to build large or small structures to complex atomic specifications.

We discuss the role of linguistic metaphors as a cognitive frame for the understanding of genetic information processing. The essential similarity between language and genetic information processing has been recognized since the very beginning, and many prominent scholars have noted the possibility of considering genes and genomes as texts or languages. Most of the core terms in molecular biology are based on linguistic metaphors. The processing of genetic information is understood as some operations on text – writing, reading and editing (...) and their specification (encoding/decoding, proofreading, transcription, translation, reading frame). The concept of gene reading can be traced from the archaic idea of the equation of Life and Nature with the Book. Thus, the genetics itself can be metaphorically represented as some operations on text (deciphering, understanding, codebreaking, transcribing, editing, etc.), which are performed by scientists. At the same time linguistic metaphors portrayed gene entities also as having the ability of reading. In the case of such “bio-reading” some essential features similar to the processes of human reading can be revealed: this is an ability to identify the biochemical sequences based on their function in an abstract system and distinguish between type and its contextual tokens of the same type. Metaphors seem to be an effective instrument for representation, as they make possible a two-dimensional description: biochemical by its experimental empirical results and textual based on the cognitive models of comprehension. In addition to their heuristic value, linguistic metaphors are based on the essential characteristics of genetic information derived from its dual nature: biochemical by its substance, textual (or quasi-textual) by its formal organization. It can be concluded that linguistic metaphors denoting biochemical objects and processes seem to be a method of description and explanation of these heterogeneous properties. (shrink)

Cryo‐electron microscopy allows the visualization of macromolecules in their native state. Combined with techniques of three‐dimensional reconstruction, cryo‐EM images of single molecules can be used to study macromolecular interactions. The ribosome, a large RNA–protein complex with multiple binding interactions, is an excellent test case illustrating the power of these new techniques. Conformational changes during the binding of tRNA and protein factors to the ribosome can now be studied without the interference of crystal packing. Now that the first X‐ray structures of (...) ribosomal subunits have become available, conformational changes observed by cryo‐EM in different functional states can be traced back to internal rearrangements of the underlying structural framework. Electron microscopy, X‐ray crystallography, and modeling should be used together in the endeavor to understand the functioning of the translational machinery. BioEssays 23:725–732, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The formation of mature large rRNAs from larger primary transcripts is very different in bacterial and mammalian cells. In both, cotranscription can help to assure the coordinated production of various rRNA species. However, in bacteria, processing is ordered, initiated by cleavages at double‐stranded stems which enclose the mature sequences; several cleavages are required to produce each mature terminus; and the final steps occur in polysomes, apparently linked to continued protein synthesis. In mouse cells, in contrast, cleavages generate nearly all mature (...) termini stochastically and directly, with no evidence for double‐stranded stems as cleavage signals; and processing occurs in the nucleolus, long before any new rRNA chains arrive in polysomes. Spacer sequences also serve different potnetial functions at the evolutionary extremes. In bacteria, transcribed spacer sequences are associated with different secondary structures in the pre‐rRNA compared to the mature rRNA, and these may promote ribosome formation. In mammalian cells, analyses are too premature to assign any comparable function to transcribed spacer sequences, but the non‐transcribed spacers are probably critical in the organization and replication of nucleoli, functions that are absent from bacteria. (shrink)

We discuss the role of linguistic metaphors as a cognitive frame for the understanding of genetic information processing. The essential similarity between language and genetic information processing has been recognized since the very beginning, and many prominent scholars have noted the possibility of considering genes and genomes as texts or languages. Most of the core terms in molecular biology are based on linguistic metaphors. The processing of genetic information is understood as some operations on text – writing, reading and editing (...) and their specification (encoding/decoding, proofreading, transcription, translation, reading frame). The concept of gene reading can be traced from the archaic idea of the equation of Life and Nature with the Book. Thus, the genetics itself can be metaphorically represented as some operations on text (deciphering, understanding, codebreaking, transcribing, editing, etc.), which are performed by scientists. At the same time linguistic metaphors portrayed gene entities also as having the ability of reading. In the case of such “bio-reading” some essential features similar to the processes of human reading can be revealed: this is an ability to identify the biochemical sequences based on their function in an abstract system and distinguish between type and its contextual tokens of the same type. Metaphors seem to be an effective instrument for representation, as they make possible a two-dimensional description: biochemical by its experimental empirical results and textual according to the cognitive models of comprehension. In addition to their heuristic value, linguistic metaphors are based on the essential characteristics of genetic information derived from its dual nature: biochemical by its substance, textual (or quasitextual) by its formal organization. It can be concluded that linguistic metaphors denoting biochemical objects and processes seem to be a method of description and explanation of these heterogeneous properties. (shrink)

We discuss the role of linguistic metaphors as a cognitive frame for the understanding of genetic information processing. The essential similarity between language and genetic information processing has been recognized since the very beginning, and many prominent scholars have noted the possibility of considering genes and genomes as texts or languages. Most of the core terms in molecular biology are based on linguistic metaphors. The processing of genetic information is understood as some operations on text – writing, reading and editing (...) and their specification (encoding/decoding, proofreading, transcription, translation, reading frame). The concept of gene reading can be traced from the archaic idea of the equation of Life and Nature with the Book. Thus, the genetics itself can be metaphorically represented as some operations on text (deciphering, understanding, code-breaking, transcribing, editing, etc.), which are performed by scientists. At the same time linguistic metaphors portrayed gene entities also as having the ability of reading. In the case of such “bio-reading” some essential features similar to the processes of human reading can be revealed: this is an ability to identify the biochemical sequences based on their function in an abstract system and distinguish between type and its contextual tokens of the same type. Metaphors seem to be an effective instrument for representation, as they make possible a two-dimensional description: biochemical by its experimental empirical results and textual based on the cognitive models of comprehension. In addition to their heuristic value, linguistic metaphors are based on the essential characteristics of genetic information derived from its dual nature: biochemical by its substance, textual (or quasi-textual) by its formal organization. It can be concluded that linguistic metaphors denoting biochemical objects and processes seem to be a method of description and explanation of these heterogeneous properties. (shrink)

It has been known for 20 years that the ribosomal protein S6 is rapidly phosphorylated when cells are stimulated to grow or divide. Furthermore, numerous studies have documented that there is a strong correlation between increases in S6 phosphorylation and protein synthesis, leading to the idea that S6 phosphorylation is involved in up‐regulating translation. In an attempt to define a mechanism by which S6 phosphorylation exerts translational control, other studies have focused on characterizing the sites of phosphorylation of this protein (...) and its location within the ribosome. Recent data show that S6 is a protein which may have diverse cellular functions and is essential for normal development, and that it may be involved in the translational regulation of a specific class of messages. (shrink)

There are currently three major theories on the origin and evolution of the genetic code: the stereochemical theory, the coevolution theory, and the error-minimization theory. The first two assume that the genetic code originated respectively from chemical affinities and from metabolic relationships between codons and amino acids. The error-minimization theory maintains that in primitive systems the apparatus of protein synthesis was extremely prone to errors, and postulates that the genetic code evolved in order to minimize the deleterious effects of the (...) translation errors. This article describes a fourth theory which starts from the hypothesis that the ancestral genetic code was ambiguous and proposes that its evolution took place with a mechanism that systematically reduced its ambiguity and eventually removed it altogether. This proposal is distinct from the stereochemical and the coevolution theories because they do not contemplate any ambiguity in the genetic code, and it is distinct from the error-minimization theory because ambiguity-reduction is fundamentally different from error-minimization. The concept of ambiguity-reduction has been repeatedly mentioned in the scientific literature, but so far it has remained only an abstract possibility because no model has been proposed for its mechanism. Such a model is described in the present article and may be the first step in a new approach to the study of the evolution of the genetic code. (shrink)

Life appears to be a natural property of matter, but the problem of its origin only arose after early scientists refuted continuous spontaneous generation. There is no chance of life arising ‘all at once’, we need the standard scientific incremental explanation with large numbers of small steps, an approach used in both physical and evolutionary sciences. The necessity for considering both theoretical and experimental approaches is emphasized. After describing basic principles that are available (including the Darwin-Eigen cycle), the search for (...) origins is considered under four main themes. These are the RNA-world hypothesis; potential intermediates between an RNA-world and a modern world via the evolution of protein synthesis and then of DNA; possible alternatives to an RNA-world; and finally the earliest stages from the simple prebiotic systems to RNA. The triplicase/proto-ribosome theory for the origin of the ribosome is discussed where triples of nucleotides are added to a replicating RNA, with the origin of a triplet code well-before protein synthesis begins. The length of the code is suggested to arise from the early development of a ratchet mechanism that overcomes the problem of continued processivity of an RNA-based RNA-polymerase. It is probable that there were precursor stages to RNA with simpler sugars, or just two nucleotides, but we do not yet know of any better alternatives to RNA that were likely to arise naturally. For prebiotic stages (before RNA) a flow-reactor model is suggested to solve metabolism, energy gradients, and compartmentation simultaneously – thus the intense interest in some form of flow reactor. If an autocatalytic cycle could arise in such a system we would be major steps ahead. The most likely physical conditions for the origin of life require further clarification and it is still unclear whether the origin of life is more of an entropy (information) problem (and therefore high temperatures would be detrimental), rather than a kinetic problem (where high temperatures may be advantageous). (shrink)

The cellular internal ribosomal entry site (IRES) is one of the most important elements to mediate cap‐independent translational initiation, especially under conditions of stress and pathology. However, a high‐throughput method to discover IRESs in these conditions is still lacking. Here, a possible way IRES long‐read sequencing based on the latest high‐throughput technologies is proposed to solve this problem. Based on this design, diversity and integrity of the transcriptome from original samples can be kept. The micro‐environment that stimulates or inhibits IRES (...) activity can also be mimicked. By using long read‐length sequencing technology, additional experiments that are essential for ruling out the cryptic promoters or splicing events in routine IRES identification processes can be circumvented. It is hoped that this proposed methodology may be adopted for IRES element discovery, hence uncovering the full extent of the role of IRESs in disease, development, and stress. Also see the video abstract here https://youtu.be/JuWBbMzWXS8. (shrink)

Mitochondria are increasingly being recognized as information hubs that sense cellular changes and transmit messages to other cellular components, such as the nucleus, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes. Nonetheless, the interaction between mitochondria and the nucleus is of special interest because they both host part of the cellular genome. Thus, the communication between genome‐bearing organelles would likely include gene expression regulation. Multiple nuclear‐encoded proteins have been known to regulate mitochondrial gene expression. On the contrary, no mitochondrial‐encoded (...) factors are known to actively regulate nuclear gene expression. MOTS‐c (mitochondrial open reading frame of the 12S ribosomal RNA type‐c) is a recently identified peptide encoded within the mitochondrial 12S ribosomal RNA gene that has metabolic functions. Notably, MOTS‐c can translocate to the nucleus upon metabolic stress (e.g., glucose restriction and oxidative stress) and directly regulate adaptive nuclear gene expression to promote cellular homeostasis. It is hypothesized that cellular fitness requires the coevolved mitonuclear genomes to coordinate adaptive responses using gene‐encoded factors that cross‐regulate the opposite genome. This suggests that cellular gene expression requires the bipartite split genomes to operate as a unified system, rather than the nucleus being the sole master regulator. (shrink)

The egg behaves as a prospective cell sustaining the developmental processes of the future embryo. In biosemiotic terms, this apparent teleonomic behaviour can be accounted for without referring to the exclusive causal role played by its genetic makeup. We envision two different processes that are uniquely found in the oocyte: (1) the first involves the mechanisms by which large amounts of mRNA accumulate in the ooplasm to establish the embryo axes prior to fertilization; (2) the second involves transfer of an (...) excess of maternally supplied ribosomes to the oocyte to provide the future embryo with newly synthesized proteins. In this paper, we argue that the information required to sustain embryonic development is not due to any physical properties of the zygotic DNA and the maternal mRNAs, but to their spatially and temporally ordered relationship in the zygote’s internal space. (shrink)

Complexes of two or more proteins form many, if not most, of the intracellular “machines” that execute physical and chemical work, and transmit information. Complexes can form from stochastic post‐translational interactions of fully formed proteins, but recent attention has shifted to co‐translational interactions in which the most common mechanism involves binding of a mature constituent to an incomplete polypeptide emerging from a translating ribosome. Studies in yeast have revealed co‐translational interactions during formation of multiple major complexes, and together with recent (...) mammalian cell studies, suggest widespread utilization of the mechanism. These translation‐dependent interactions can involve a single or multiple mRNA templates, can be uni‐ or bi‐directional, and can use multi‐protein sub‐complexes as a binding component. Here, we discuss benefits of co‐translational complex assembly including accuracy and efficiency, overcoming hidden interfaces, localized and hierarchical assembly, and reduction of orphan protein degradation, toxicity, and dominant‐negative pathogenesis, all serving to improve cell fitness. (shrink)

The coupling of protein synthesis and folding is a crucial yet poorly understood aspect of cellular protein folding. Over the past few years, it has become possible to experimentally follow and define protein folding on the ribosome, revealing principles that shape co‐translational folding and distinguish it from refolding in solution. Here, we highlight some of these recent findings from biochemical and biophysical studies and their potential significance for cellular protein biogenesis. In particular, we focus on nascent chain interactions with the (...) ribosome, interactions within the nascent protein, modulation of translation elongation rates, and the role of mechanical force that accompanies nascent protein folding. The ability to obtain mechanistic insight in molecular detail has set the stage for exploring the intricate process of nascent protein folding. We believe that the aspects discussed here will be generally important for understanding how protein synthesis and folding are coupled and regulated. (shrink)

Post‐transcriptional tRNA modifications contribute to the decoding efficiency of tRNAs by supporting codon recognition and tRNA stability. Recent work shows that the molecular and cellular functions of tRNA modifications and tRNA‐modifying‐enzymes are linked to brain development and neurological disorders. Lack of these modifications affects codon recognition and decoding rate, promoting protein aggregation and translational stress response pathways with toxic consequences to the cell. In this review, we discuss the peculiarity of local translation in neurons, suggesting a role for fine‐tuning of (...) translation performed by tRNA modifications. We provide several examples of tRNA modifications involved in physiology and pathology of the nervous system, highlighting their effects on protein translation and discussing underlying mechanisms, like the unfolded protein response (UPR), ribosome quality control (RQC), and no‐go mRNA decay (NGD), which could affect neuronal functions. We aim to deepen the understanding of the roles of tRNA modifications and the coordination of these modifications with the protein translation machinery in the nervous system. (shrink)

Graphical AbstractYeast mitochondria frequently mutate, and some dysfunctional mitochondria out-compete wild-type versions. The retrograde response enables yeast to tolerate dysfunction, but also produces ribosomal DNA circles (ERCs). We propose that ERC accumulation increases expression of the rDNA antisense gene, TAR1, which counteracts spread of respiration-deficient mitochondria in matings with wild-type yeast.

Over the last decade, our appreciation of the importance of the nucleolus for cellular function has progressed from the ordinary to the extraordinary. We no longer think of the nucleolus as simply the site of ribosome production, or a dynamic subnuclear body noted by pathologists for its changes in size and shape with malignancy. Instead, the nucleolus has emerged as a key controller of many cellular processes that are fundamental to normal cell homeostasis and the target for dysregulation in many (...) human diseases; in some cases, independent of its functions in ribosome biogenesis. These extra‐nucleolar or new functions, which we term “non‐canonical” to distinguish them from the more traditional role of the nucleolus in ribosome synthesis, are the focus of this review. In particular, we explore how these non‐canonical functions may provide novel insights into human disease and in some cases new targets for therapeutic development. (shrink)

Bacteria use trans‐translation to rescue stalled ribosomes and target incomplete proteins for proteolysis. Despite similarities between tRNAs and transfer‐messenger RNA (tmRNA), the key molecule for trans‐translation, new structural and biochemical data show important differences between translation and trans‐translation at most steps of the pathways. tmRNA and its binding partner, SmpB, bind in the A site of the ribosome but do not trigger the same movements of nucleotides in the rRNA that are required for codon recognition by tRNA. tmRNA‐SmpB moves (...) from the A site to the P site of the ribosome without subunit rotation to generate hybrid states, and moves from the P site to a site outside the ribosome instead of to the E site. During catalysis, transpeptidation to tmRNA appears to require the ribosomal protein bL27, which is dispensable for translation, suggesting that this protein may be conserved in bacteria due to trans‐translation. These differences provide insights into the fundamental nature of trans‐translation, and provide targets for new antibiotics that may have decrease cross‐reactivity with eukaryotic ribosomes. (shrink)

Ribosomal RNA transcription was one of the first model systems for molecular characterization of a transcription regulatory mechanism and certainly one of the best studied in the widest range of organisms. In multicellular organisms, however, the issue of cell‐type‐specific regulation of rRNA transcription has not been well addressed. Here I propose that a systematic study of cell‐type‐specific regulation of rRNA transcription may reveal new regulatory mechanisms that have not been previously realized. Specifically, issues concerning the cell‐type‐specific requirement for rRNA production, (...) the universality of Pol I transcription complex and the division of rDNA into regulatory subdomains are discussed. BioEssays 28: 719–725, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Electron micrographs of active ribosomal genes from many species show a similar picture in which gene regions covered with nascent transcripts alternate with apparently non‐transcribed spacers. Since the gradients of visible nascent transcripts stop near the 3′ end of the 28S sequence it has often been assumed that transcription by RNA polymerase I also terminates at that point. Recent biochemical studies have shown however, that transcription continues far beyond the 3′ end of the 28S and in some species continues across (...) the entire spacer. In this article we review the evidence for spacer transcription in Xenopus, mouse and Drosophila and discuss possible reasons for its invisibility in the electron microscope. (shrink)

Graphical AbstractCellular internal ribosomal entry site (IRES) is important for cap-independent translational initiation during stress and pathology. In article number 1900180, Lei-Yun Wang et al. propose an idea to discover IRES based on the latest high-throughput technologies, hence facilitating the understanding of IRES in disease development and treatment.

The development of synthetic biology calls for accurate understanding of the critical functions that allow construction and operation of a living cell. Besides coding for ubiquitous structures, minimal genomes encode a wealth of functions that dissipate energy in an unanticipated way. Analysis of these functions shows that they are meant to manage information under conditions when discrimination of substrates in a noisy background is preferred over a simple recognition process. We show here that many of these functions, including transporters and (...) the ribosome construction machinery, behave as would behave a material implementation of the informationmanaging agent theorized by Maxwell almost 150 years ago and commonly known as Maxwell’s demon (MxD). A core gene set encoding these functions belongs to the minimal genome required to allow the construction of an autonomous cell. These MxDs allow the cell to perform computations in an energy-efficient way that is vastly better than our contemporary computers. (shrink)

Prokaryotes are generally assumed to be the oldest existing form of life on earth. This assumption, however, makes it difficult to understand certain aspects of the transition from earlier stages in the origin of life to more complex ones, and it does not account for many apparently ancient features in the eukaryotes. From a model of the RNA world, based on relic RNA species in modern organisms, one can infer that there was an absolute requirement for a high-accuracy RNA replicase (...) even before proteins evolved. In addition, we argue here that the ribosome (together with the RNAs involved in its assembly) is so large that it must have had a prior function before protein synthesis. A model that connects and equates these two requirements (high-accuracy RNA replicase and prior function of the ribosome) can explain many steps in the origin of life while accounting for the observation that eukaryotes have retained more vestiges of the RNA world. The later derivation of prokaryote RNA metabolism and genome structure can be accounted for by the two complementary mechanisms of r-selection and thermoreduction. BioEssays 21:880–889, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Bivalent chromatin with active H3K4me3 and repressive H3K27me3 was initially identified in embryonic stem cells (ESCs) to poise expression of developmental genes upon lineage commitment. Since then, many more different bivalent modifications have been demonstrated in both ESCs and fully differentiated cells. Bivalency not only spatiotemporally controls gene transcription but also acts to fine‐tune the level of transcription during development. Although increasing number of studies demonstrated the functional significance of bivalent chromatin, the molecular connection of bivalent chromatin and transcriptional regulation (...) remains largely elusive. Recently, we showed Spindlin1/C11orf84 complex prefers to recognize the non‐canonical histone H3K4me3K9me3 bivalent mark, which is required for timely ribosomal RNA transcription. Here, we hypothesize the recognition of K4me3 and K9me3 at the same histone tail by Spindlin1/C11orf84 complex may serve as a general mechanism of conversion from a repressed to an active chromatin structure for transcriptional activation. (shrink)

Insect molting is elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands. Ecdysteroid synthesis in the prothoracic glands is controlled in large measure by a peptide hormone from the brain, prothoracicotropic hormone (PTTH), which exists in two forms and is released into the general circulation as a result of environmental and developmental cues. The means by which PTTH activates the prothoracic glands has been examined at the cellular level and the data reveal the involvement of (...) cAMP, calcium, calmodulin, cAMP‐dependent protein kinase and the ultimate phosphorylation of a 34 kDa protein tentatively identified as ribosomal protein S6. (shrink)

A complex structure, visible by electron microscopy, surrounds each chromosome during mitosis. The organization of this structure is distinct from that of the chromosomes and the cytoplasm. It forms a perichromosomal layer that can be isolated together with the chromosomes. This layer covers the chromosomes except in centromeric regions. The perichromosomal layer includes nuclear and nucleolar proteins as well as ribonucleoproteins (RNPs). The list of proteins and RNAs identified includes nuclear matrix proteins (perichromin, peripherin), nucleolar proteins (perichro‐monucleolin, Ki‐67 antigen, B23 (...) protein, fibrillarin, p103, p52), ribosomal proteins (S1) and snRNAs (U3 RNAs). Only limited information is available about how and when the perichromosomal layer is formed. During early prophase, the proteins extend from the nucleoli towards the periphery of the nucleus. Thin cordon‐like structures reach the nuclear envelope delimiting areas in which chromosomes condense. At telophase, the proteins are associated with the part of the chromosomes remaining condensed and accumulate in newly formed nucleoli in regions where chromatin is already decondensed. The perichromosomal layer contains several different classes of proteins and RNPs and it has been attributed various roles: (1) in chromosome organization, (2) as a barrier around the chromosomes, (3) involvement in compartmentation of the cells in prophase and telophase and (4) a binding site for chromosomal passenger proteins necessary to the early process of nuclear assembly. (shrink)

The universally recognized backbone of molecular biology describes the flow of genetic information from deoxyribonucleic acid (DNA) to ribonucleic acid (RNA) to protein or gene product, that is, DNA is transcribed into another nucleic acid (RNA), which is single stranded, next some types of RNA are in turn translated into proteins. Translation of nucleic acids to proteins is literally a translation from the genomic language to the metabolic language. Codons formed of a sequence of three nucleic acids summon a specific (...) amino acid. Translation from codons to proteins, that is, protein synthesis, takes place by specialized machinery comprising mRNA, ribosomes, and free amino acids. Inferring the structure of DNA opened the door for tremendous advances in understanding the role of genes in creating life, directing replication, and ongoing metabolic processes responsible for maintaining life at both the cellular and organism level. (shrink)

Dyskeratosis congenita is a rare skin and bone marrow failure syndrome caused by defective telomere maintenance in stem cells. The major X‐linked form of the disease is due to mutations in a nucleolar protein, dyskerin, that is part of small nucleolar ribonucleoprotein particles that are involved in processing ribosomal RNA. It is also found in the telomerase complex, pointing to an unexpected link between these two processes. An autosomal dominant form is due to mutations in the RNA component of telomerase (...) (hTR). Patients with this form of the disease are more severely affected in later generations that carry the mutations, possibly due to the inheritance of shortened telomeres, disguising the inherited nature of the disease in some cases classified as aplastic anemia. Because of the importance of telomerase in tumour formation and aging, study of this disease may provide important clues about these fundamental processes. BioEssays 25:126–133, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Metagenomics bears upon all aspects of microbiology, including our understanding of mitochondrial and eukaryote origin. Recently, ribosomal protein phylogenies show the eukaryote host lineage – the archaeal lineage that acquired the mitochondrion – to branch within the archaea. Metagenomic studies are now uncovering new archaeal lineages that branch more closely to the host than any cultivated archaea do. But how do they grow? Carbon and energy metabolism as pieced together from metagenome assemblies of these new archaeal lineages, such as the (...) Deep Sea Archaeal Group (including Lokiarchaeota) and Bathyarchaeota, do not match the physiology of any cultivated microbes. Understanding how these new lineages live in their environment is important, and might hold clues about how mitochondria arose and how the eukaryotic lineage got started. Here we look at these exciting new metagenomic studies, what they say about archaeal physiology in modern environments, how they impact views on host‐mitochondrion physiological interactions at eukaryote origin. (shrink)

Recently, constructive neutral evolution has been touted as an important concept for the understanding of the emergence of cellular complexity. It has been invoked to help explain the development and retention of, amongst others, RNA splicing, RNA editing and ribosomal and mitochondrial respiratory chain complexity. The theory originated as a welcome explanation of isolated small scale cellular idiosyncrasies and as a reaction to ‘overselectionism’. Here I contend, that in its extended form, it has major conceptual problems, can not explain observed (...) patterns of complex processes, is too easily dismissive of alternative selectionist models, underestimates the creative force of complexity as such, and – if seen as a major evolutionary mechanism for all organisms – could stifle further thought regarding the evolution of highly complex biological processes. (shrink)

The origin of the bilaterian metazoans from radial ancestors is one of the biggest puzzles in animal evolution. A way to solve it is to identify the nature and main features of the last common ancestor of the bilaterians (LCB). Recent progress in molecular phylogeny has shown that many platyhelminth flatworms, regarded for a long time as basal bilaterians, now belong to the lophotrochozoan protostomates. In contrast, the LCB is now considered a complex organism bearing several features of modern bilaterians. (...) Here we discuss an alternative view, in which acoelomorph (Acoela + Nemertodermatida) flatworms, which do not belong to the Platyhelminthes, represent the earliest extant bilaterian clade. Sequences from ribosomal and other nuclear genes, Hox cluster genes, and reinterpretation of some morphological features strongly support the basal position of acoelomorphs arguing against a complex LCB. This reconstruction backs the old planuloid–acoeloid hypothesis and may help our understanding of the evolution of body axes, Hox genes and the Cambrian explosion. BioEssays 26:1046–1057, 2004. © 2004 Wiley Periodicals, Inc. (shrink)