Translation Of Genetic Information Research Articles

Nucleic acid drug and delivery techniques for disease therapy: Present situation and future prospect

AbstractOver the two decades, RNA drugs have gradually made their way from bench to bed. Initially, RNA was not an ideal drug since RNA molecules degrade easily and have a relatively short half‐life in the circulation system. Nevertheless, the chemical modification extended the half‐life of RNA in recent years, which makes RNA drugs a new star in drug discovery industry. RNA molecules hold many properties that facilitate their application as therapeutic drugs. RNAs could fold to form complex conformations to bind to proteins, small molecules, or other nucleic acids, and some even form catalytic centers. Protein‐encoding RNAs are the carriers of genetic information from DNA to ribosomes, and various types of non‐coding RNAs cooperate in the transcription and translation of genetic information through various mechanisms. To date, three mainstream RNA therapies have drawn widespread attention: (1) messenger RNA that encodes therapeutic proteins or vaccine antigens; (2) small interfering RNA, microRNA (miRNA), antisense oligonucleotides that inhibit the activity of pathogenic RNAs; and (3) aptamers that regulate protein activity. Here, we summarized the current research and perspectives of RNA therapies, which may provide innovative highlights for cancer therapy.

The spiderweb of error-detecting codes in the genetic information

Nature possesses inherent mechanisms for error detection and correction during the translation of genetic information, as demonstrated by the discovery of a self-complementary circular C3-code called X0 in various organisms such as bacteria, eukaryotes, plasmids, and viruses (Arquès and Michel, 1996; Michel, 2015, 2017). Since then, extensive research has focused on circular codes, which are believed to be remnants of ancient comma-free codes. These codes can be regarded as an additional genetic code specifically optimized for detecting and preserving the proper reading frame in protein-coding sequences. A study by Fimmel et al. in 2014 identified that a total of 216 maximal self-complementary C3-codes can be grouped into 27 equivalence classes with eight codes in each class.In this work, we study how the 27 equivalence classes are related to each other. While the codes in each equivalence class obtained by Fimmel et al. in 2014 are permutations of each other, i.e. one code can be obtained from the other by applying a permutation of the bases, it has not been clear how the equvalence classes are connected. We show that there is an ordering of the equivalence classes such that one gets from one class to the next one by substituting only one pair of codon/anticodon in the corresponding codes, i.e. the corresponding codes have a maximal intersection of 18 codons. To perform this analysis, we define two graphs, G216 and G27, whose vertices are, respectively, all 216 maximal self-complementary C3-codes and 27 equivalence classes. Several properties of the graphs are obtained. Most surprisingly, it turns out that G27 contains Hamiltonian paths of length 27. This fact ultimately leads to a representation of the set of all 216 maximal self-complementary C3-codes as a kind of spider web. Finally, we define dinucleotide cuts of such codes by projecting each codon to its first two bases and show that the paths of lengths 27 in G216 can even be chosen so that all the codes contain a special subset of dinucleotides defined by Rumer’s roots. These observations raise a lot of new questions about the biological function of such structures.

Regulation of Leaderless mRNA Translation in Bacteria.

In bacteria, the translation of genetic information can begin through at least three different mechanisms: canonical or Shine-Dalgarno-led initiation, readthrough or 70S scanning initiation, or leaderless initiation. Here, we discuss the main features and regulation of the last, which is characterized mainly by the ability of 70S ribosomal particles to bind to AUG located at or near the 5′ end of mRNAs to initiate translation. These leaderless mRNAs (lmRNAs) are rare in enterobacteria, such as Escherichia coli, but are common in other bacteria, such as Mycobacterium tuberculosis and Deinococcus deserti, where they may represent more than 20% and even up to 60% of the genes. Given that lmRNAs are devoid of a 5′ untranslated region and the Shine-Dalgarno sequence located within it, the mechanism of translation regulation must depend on molecular strategies that are different from what has been observed in the Shine-Dalgarno-led translation. Diverse regulatory mechanisms have been proposed, including the processing of ribosomal RNA and changes in the abundance of translation factors, but all of them produce global changes in the initiation of lmRNA translation. Thus, further research will be required to understand how the initiation of the translation of particular lmRNA genes is regulated.

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight.

Malignant pleural mesothelioma (MPM) is the epitome of a recalcitrant cancer driven by pharmacologically intractable tumor suppressor proteins. A significant but largely unmet challenge in the field is the translation of genetic information on alterations in tumor suppressor genes (TSGs) into effective cancer-specific therapies. The notion that abnormal tumor genome subverts physiological cellular processes, which creates collateral vulnerabilities contextually related to specific genetic alterations, offers a promising strategy to target TSG-driven MPM. Moreover, emerging evidence has increasingly appreciated the therapeutic potential of genetic and pharmacological dependencies acquired en route to cancer development and drug resistance. Here, we review the most recent progress on vulnerabilities co-selected by functional loss of major TSGs and dependencies evolving out of cancer development and resistance to cisplatin based chemotherapy, the only first-line regimen approved by the US Food and Drug Administration (FDA). Finally, we highlight CRISPR-based functional genomics that has emerged as a powerful platform for cancer drug discovery in MPM. The repertoire of MPM-specific “Achilles heel” rises on the horizon, which holds the promise to elucidate therapeutic landscape and may promote precision oncology for MPM.

Recent Advances: Molecular Mechanism of RNA Oxidation and Its Role in Various Diseases.

Compared with the research on DNA damage, there are fewer studies on RNA damage, and the damage mechanism remains mostly unknown. Recent studies have shown that RNA is more vulnerable to damage than DNA when the cells are exposed to endogenous and exogenous insults. RNA injury may participate in a variety of disease occurrence and development. RNA not only has important catalytic functions and other housekeeping functions, it also plays a decisive role in the translation of genetic information and protein biosynthesis. Various kinds of stressors, such as ultraviolet, reactive oxygen species and nitrogen, can cause damage to RNA. It may involve in the development and progression of diseases. In this review, we focused on the relationship between the RNA damage and disease as well as the research progress on the mechanism of RNA damage, which is of great significance for the pathogenesis, diagnosis, and treatment of related diseases.

Relationship between genetic knowledge and familial communication of CRC risk and intent to communicate CRCP genetic information: insights from FamilyTalk eMERGE III.

Successful translation of genetic information into patient-centered care and improved outcomes depends, at least in part, on patients' genetic knowledge. Although genetic knowledge is believed to be an important facilitator of familial communication of genetic risk information, empirical evidence of this association is lacking. We examined whether genetic knowledge was related to frequency of current familial communication about colorectal cancer and polyp (CRCP) risk, and future intention to share CRCP-related genomic test results with family members in a clinical sample of patients. We recruited 189 patients eligible for clinical CRCP sequencing to the eMERGE III FamilyTalk randomized controlled trial and surveyed them about genetic knowledge and familial communication at baseline. Participants were primarily Caucasian, 47% male, average age of 68 years, mostly well educated, and with high-income levels. Genetic knowledge was positively associated with future-intended familial communication of genetic information (odds ratio = 1.11, 95% confidence interval: 1.02-1.23), but not associated with current communication of CRC risk (β = 0.01, p = .58). Greater current communication of CRC risk was associated with better family functioning (β = 0.04, p = 8.2e-5). Participants' genetic knowledge in this study was minimally associated with their intended familial communication of genetic information. Although participants have good intentions of communication, family-level factors may hinder actual follow through of these intentions. Continued focus on improving proband's genetic knowledge coupled with interventions to overcome family-level barriers to communication may be needed to improve familial communication rates.

Assessing Stakeholder Perceptions of the Utility of Genetic Information for the Clinical Care of Mental Health Disorders: We Have a Will but Need to See the Way.

Academic stakeholders' (primarily mental health researchers and clinicians) practices and attitudes related to the translation of genetic information into mental health care were assessed. A three-part survey was administered at two large, urban universities. Response frequencies were calculated. Participants (N = 64) reported moderate levels of translational practice, adequate levels of genetic knowledge, and variable levels of genetic competence. They held positive attitudes toward translating genetic information about mental health broadly but negative attitudes about the impact that such information would have on specific aspects of care. The current study lays the groundwork for further inquiry into translating genetic information to mental health care.

Identification of biological mechanisms underlying a multidimensional ASD phenotype using machine learning

The complex genetic architecture of Autism Spectrum Disorder (ASD) and its heterogeneous phenotype makes molecular diagnosis and patient prognosis challenging tasks. To establish more precise genotype–phenotype correlations in ASD, we developed a novel machine-learning integrative approach, which seeks to delineate associations between patients’ clinical profiles and disrupted biological processes, inferred from their copy number variants (CNVs) that span brain genes. Clustering analysis of the relevant clinical measures from 2446 ASD cases in the Autism Genome Project identified two distinct phenotypic subgroups. Patients in these clusters differed significantly in ADOS-defined severity, adaptive behavior profiles, intellectual ability, and verbal status, the latter contributing the most for cluster stability and cohesion. Functional enrichment analysis of brain genes disrupted by CNVs in these ASD cases identified 15 statistically significant biological processes, including cell adhesion, neural development, cognition, and polyubiquitination, in line with previous ASD findings. A Naive Bayes classifier, generated to predict the ASD phenotypic clusters from disrupted biological processes, achieved predictions with a high precision (0.82) but low recall (0.39), for a subset of patients with higher biological Information Content scores. This study shows that milder and more severe clinical presentations can have distinct underlying biological mechanisms. It further highlights how machine-learning approaches can reduce clinical heterogeneity by using multidimensional clinical measures, and establishes genotype–phenotype correlations in ASD. However, predictions are strongly dependent on patient’s information content. Findings are therefore a first step toward the translation of genetic information into clinically useful applications, and emphasize the need for larger datasets with very complete clinical and biological information.

Tautomerism of Guanine Analogues.

Tautomerism of nucleic acid (NA) bases is a crucial factor for the maintenance and translation of genetic information in organisms. Only canonical tautomers of NA bases can form hydrogen-bonded complexes with their natural counterparts. On the other hand, rare tautomers of nucleobases have been proposed to be involved in processes catalysed by NA enzymes. Isocytosine, which can be considered as a structural fragment of guanine, is known to have two stable tautomers both in solution and solid states. The tautomer equilibrium of isocytosine contrasts with the remarkable stability of the canonical tautomer of guanine. This paper investigates the factors contributing to the stability of the canonical tautomer of guanine by a combination of NMR experiments and theoretical calculations. The electronic effects of substituents on the stability of the rare tautomers of isocytosine and guanine derivatives are studied by density functional theory (DFT) calculations. Selected derivatives are studied by variable-temperature NMR spectroscopy. Rare tautomers can be stabilised in solution by intermolecular hydrogen-bonding interactions with suitable partners. These intermolecular interactions give rise to characteristic signals in proton NMR spectra, which make it possible to undoubtedly confirm the presence of a rare tautomer.

Kurze Peptide regulieren die Aktivität bakterieller Ribosomen

In all living cells ribosomes are responsible for the translation of genetic information into the corresponding protein sequence. This central position does not only make them a valuable target for antibiotics but also offers great possibilities to regulate gene expression. This article addresses two distinct mechanisms of ribosomal activity regulation: via short nascent peptides (regulation in cis) and via proline-rich antimicrobial peptides (regulation in trans).

Physiological mechanism epistatic interaction of resistance genes to acaricides of various chemical classes in the interline hybrids of two-spotted spider mite

Summary: Background. The presence in interline hybrids two-spotted spider mite Tetranychus urticae Koch two genes determining resistance to acaricides of various chemical classes significantly increases their sensitivity to the action of each these toxicants.
 Materials and methods. The resistant and susceptible to malathion, bifenthrin and abamectin inbred lines of spider mite by disruptive selection cycles were obtained. The toxicological tests were performed by diagnostic concentrations of acaricides. The protein marker gene of resistance to malathion was determined by poliacrylamide disc-electrophoresis.
 Results. The epistatic interaction of resistance genes to different acaricides is not manifestation at the stages of transcription and translation of genetic information.
 Conclusion. The epistatic effect of another gene on the resistance gene to the current acaricide is a different consequence of metabolism processes encoded by each gene at the stage of phenotypic regulation.

Kinetic theory and thermodynamics of template-directed copolymerization

Template-directed copolymerization is the fundamental process for the replication, transcription, and translation of genetic information. The copy of the template sequence is grown by the attachment of monomers with a molecular machine. The long-time kinetics of such processes is exactly solvable in terms of iterated function systems. This method determines the effects of sequence heterogeneity and replication errors on the growth of the copy and the statistical properties of its sequence. In particular, a transition can occur between linear and sublinear growth in time of the copy. In the linear regime, the local growth velocity along the template may have a fractal distribution. Furthermore, the growth can be driven around equilibrium by the entropic effect of replication errors in an adverse free-energy landscape.

Expansion of Noncanonical V-Arm-Containing tRNAs in Eukaryotes

Transfer RNA (tRNA) is essential for the translation of genetic information into proteins, and understanding its molecular evolution is important if we are to understand the genetic code. In general, long variable-arm (V-arm) structures form in tRNA(Leu), tRNA(Ser), and bacterial and organellar tRNA(Tyr). However, as we have previously reported, noncanonical V-arms occur in nematode tRNA(Gly) and tRNA(Ile), and potentially affect translational fidelity. Here, we comprehensively analyzed 69 eukaryotic genome sequences and examined the evolutionary divergence of the V-arm-containing tRNAs. In total, 253 V-arm-containing tRNAs, with neither leucine nor serine anticodons, were identified in organisms ranging from nematodes to fungi, plants, and vertebrates. We defined them as "noncanonical V-arm-containing tRNAs" (nov-tRNAs). Moreover, 2,415 nov-tRNA-like sequences lacking some of the conserved features of tRNAs were also identified, largely in vertebrate genomes. These nov-tRNA/nov-tRNA-like sequences can be categorized into three types, based on differences in their possible evolutionary origins. The type A nov-tRNAs in nematodes probably evolved not only from tRNA(Leu) but also from tRNA(Ser) and other isotypes on several independent occasions. The type B nov-tRNAs are dispersed abundantly throughout vertebrate genomes, and seem to have originated from retrotransposable elements. The type C nov-tRNAs may have been acquired from plant chloroplasts or from bacteria through horizontal transfer. Our findings provide unexpected insight into the evolution of the tRNA molecule, which was diverse and occurred independently in nematodes, vertebrates, and plants.

Streamlined cell-free protein synthesis from sequence information

In this study, we describe a cell-free protein synthesis consolidated with polymerase chain reaction (PCR)-based synthetic gene assembly that allows for streamlined translation of genetic information. In silico-designed fragments of target genes were PCR-assembled and directly expressed in a cell-free synthesis system to generate functional proteins. This method bypasses the procedures required in conventional cell-based gene expression methods, integrates gene synthesis and cell-free protein synthesis, shortens the time to protein production, and allows for facile regulation of gene expression by manipulating the oligomer sequences used for gene synthesis. The strategy proposed herein expands the flexibility and throughput of the protein synthesis process, a fundamental component in the construction of synthetic biological systems.

Using tumour pathology to identify people at high genetic risk of breast and colorectal cancers

Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically-defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes.

Global and local depletion of ternary complex limits translational elongation

The translation of genetic information according to the sequence of the mRNA template occurs with high accuracy and fidelity. Critical events in each single step of translation are selection of transfer RNA (tRNA), codon reading and tRNA-regeneration for a new cycle. We developed a model that accurately describes the dynamics of single elongation steps, thus providing a systematic insight into the sensitivity of the mRNA translation rate to dynamic environmental conditions. Alterations in the concentration of the aminoacylated tRNA can transiently stall the ribosomes during translation which results, as suggested by the model, in two outcomes: either stress-induced change in the tRNA availability triggers the premature termination of the translation and ribosomal dissociation, or extensive demand for one tRNA species results in a competition between frameshift to an aberrant open-reading frame and ribosomal drop-off. Using the bacterial Escherichia coli system, we experimentally draw parallels between these two possible mechanisms.

At the dawn of the 21st century: Is dynamics the missing link for understanding enzyme catalysis?

Enzymes play a key role in almost all biological processes, accelerating a variety of metabolic reactions as well as controlling energy transduction, the transcription, and translation of genetic information, and signaling. They possess the remarkable capacity to accelerate reactions by many orders of magnitude compared to their uncatalyzed counterparts, making feasible crucial processes that would otherwise not occur on biologically relevant timescales. Thus, there is broad interest in understanding the catalytic power of enzymes on a molecular level. Several proposals have been put forward to try to explain this phenomenon, and one that has rapidly gained momentum in recent years is the idea that enzyme dynamics somehow contributes to catalysis. This review examines the dynamical proposal in a critical way, considering basically all reasonable definitions, including (but not limited to) such proposed effects as "coupling between conformational and chemical motions," "landscape searches" and "entropy funnels." It is shown that none of these proposed effects have been experimentally demonstrated to contribute to catalysis, nor are they supported by consistent theoretical studies. On the other hand, it is clarified that careful simulation studies have excluded most (if not all) dynamical proposals. This review places significant emphasis on clarifying the role of logical definitions of different catalytic proposals, and on the need for a clear formulation in terms of the assumed potential surface and reaction coordinate. Finally, it is pointed out that electrostatic preorganization actually accounts for the observed catalytic effects of enzymes, through the corresponding changes in the activation free energies.

Translation of genetic information into healthcare use

The genome era has seen the interplay of two powerful and disruptive forces in healthcare, those being genetic information and information technology. Following the investment of several billion US dollars, the international Human Genome Project provided a vast amount of information that was usually well outside of a healthcare service context. Investment in associating genetic information with human disease and disease epidemiology was limited. This disconnect has left the public unsure of when particular genetic discoveries are still in research or ready to be delivered as services. How we use genetic information in healthcare varies over the two major subdivisions of genetic information, those being acquired versus heritable disease traits. Even within the heritable diseases and traits the kinds of information needed to integrate genetics into healthcare varies over the three major categories of genetic influence, those being: (1) the usually rare Mendelian diseases with very strong genetic influences;(2) the genetic susceptibilities and predispositions with moderately strong genetic influences that are modulated by the individual’s genetic background and environmental influences;and (3) the common diseases with weak genetic influences and strong lifestyle and other environmental influences. Each area will need different strategies for educating the workforce, improving the evidence base, and developing and providing the appropriate clinical guidance to practitioners. Information technology will clearly be central to the development of an effective translational research infrastructure and has its place in all of the aforementioned areas.

Insights into and speculations about snake venom metalloproteinase (SVMP) synthesis, folding and disulfide bond formation and their contribution to venom complexity

As more data are generated from proteome and transcriptome analyses of snake venoms, we are gaining an appreciation of the complexity of the venoms and, to some degree, the various sources of such complexity. However, our knowledge is still far from complete. The translation of genetic information from the snake genome to the transcriptome and ultimately the proteome is only beginning to be appreciated, and will require significantly more investigation of the snake venom genomic structure prior to a complete understanding of the genesis of venom composition. Venom complexity, however, is derived not only from the venom genomic structure but also from transcriptome generation and translation and, perhaps most importantly, post-translation modification of the nascent venom proteome. In this review, we examine the snake venom metalloproteinases, some of the predominant components in viperid venoms, with regard to possible synthesis and post-translational mechanisms that contribute to venom complexity. The aim of this review is to highlight the state of our knowledge on snake venom metalloproteinase post-translational processing and to suggest testable hypotheses regarding the cellular mechanisms associated with snake venom metalloproteinase complexity in venoms.

The Mechanics of Translocation: A Molecular “Spring-and-Ratchet” System

The translation of genetic information into proteins is a fundamental process of life. Stepwise addition of amino acids to the growing polypeptide chain requires the coordinated movement of mRNA and tRNAs through the ribosome, a process known as translocation. Here, we review current understanding of the kinetics and mechanics of translocation, with particular emphasis on the structure of a functional mammalian ribosome stalled during translocation by an mRNA pseudoknot. In the context of a pseudoknot-stalled complex, the translocase EF-2 is seen to compress a hybrid-state tRNA into a strained conformation. We propose that this strain energy helps overcome the kinetic barrier to translocation and drives tRNA into the P-site, with EF-2 biasing this relaxation in one direction. The tRNA can thus be considered a molecular spring and EF-2 a Brownian ratchet in a “spring-and-ratchet” system within the translocation process.