-
Genes & Development Mar 2020ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its... (Review)
Review
ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its molecular functions and biological roles, as well as the activity of the ADP-ribose (ADPR) transferase enzymes (PARP family members) that catalyze it. Growing evidence indicates that PARP-mediated ADPRylation events are key regulators of the protein biosynthetic pathway, leading from rDNA transcription and ribosome biogenesis to mRNA synthesis, processing, and translation. In this review we describe the role of PARP proteins and ADPRylation in all facets of this pathway. PARP-1 and its enzymatic activity are key regulators of rDNA transcription, which is a critical step in ribosome biogenesis. An emerging role of PARPs in alternative splicing of mRNAs, as well as direct ADPRylation of mRNAs, highlight the role of PARP members in RNA processing. Furthermore, PARP activity, stimulated by cellular stresses, such as viral infections and ER stress, leads to the regulation of mRNA stability and protein synthesis through posttranscriptional mechanisms. Dysregulation of PARP activity in these processes can promote disease states. Collectively, these results highlight the importance of PARP family members and ADPRylation in gene regulation, mRNA processing, and protein abundance. Future studies in these areas will yield new insights into the fundamental mechanisms and a broader utility for PARP-targeted therapeutic agents.
Topics: ADP-Ribosylation; Animals; Gene Expression; Humans; Poly(ADP-ribose) Polymerases; Protein Biosynthesis; Protein Processing, Post-Translational; Proteostasis; RNA
PubMed: 32029452
DOI: 10.1101/gad.334433.119 -
Cold Spring Harbor Perspectives in... Dec 2012Translational control plays an essential role in the regulation of gene expression. It is especially important in defining the proteome, maintaining homeostasis, and... (Review)
Review
Translational control plays an essential role in the regulation of gene expression. It is especially important in defining the proteome, maintaining homeostasis, and controlling cell proliferation, growth, and development. Numerous disease states result from aberrant regulation of protein synthesis, so understanding the molecular basis and mechanisms of translational control is critical. Here we outline the pathway of protein synthesis, with special emphasis on the initiation phase, and identify areas needing further clarification. Features of translational control are described together with numerous specific examples, and we discuss prospects for future conceptual advances.
Topics: Bacterial Physiological Phenomena; Eukaryotic Cells; Gene Expression Regulation; Humans; MicroRNAs; Models, Biological; Protein Biosynthesis
PubMed: 23209153
DOI: 10.1101/cshperspect.a011528 -
Neuropsychopharmacology : Official... Jan 2016
Review
Topics: Animals; Humans; Protein Biosynthesis; RNA; Real-Time Polymerase Chain Reaction; Sequence Analysis, RNA
PubMed: 26657954
DOI: 10.1038/npp.2015.262 -
Brain Research Aug 2018Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of... (Review)
Review
Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of Fragile X syndrome (FXS). Excess signaling through group 1 metabotropic glutamate receptors is commonly observed in mouse models of FXS, which in part is attributed to dysregulated translation and downstream signaling. Considering the wide spectrum of cellular and physiologic functions that loss of FMRP can affect in general, it may be advantageous to pursue disease mechanism based treatments that directly target translational components or signaling factors that regulate protein synthesis. Various FMRP targets upstream and downstream of the translational machinery are therefore being investigated to further our understanding of the molecular mechanism of RNA and protein synthesis dysregulation in FXS as well as test their potential role as therapeutic interventions to alleviate FXS associated symptoms. In this review, we will broadly discuss recent advancements made towards understanding the role of FMRP in translation regulation, new pre-clinical animal models with FMRP targets located at different levels of the translational and signal transduction pathways for therapeutic intervention as well as future use of stem cells to model FXS associated phenotypes.
Topics: Animals; Dendrites; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression Regulation; Humans; Protein Biosynthesis; RNA, Messenger; Receptors, Metabotropic Glutamate; Signal Transduction
PubMed: 29653083
DOI: 10.1016/j.brainres.2018.04.008 -
Journal of Molecular Biology May 2016The ribosome is a large two-subunit ribonucleoprotein machine that translates the genetic code in all cells, synthesizing proteins according to the sequence of the mRNA... (Review)
Review
The ribosome is a large two-subunit ribonucleoprotein machine that translates the genetic code in all cells, synthesizing proteins according to the sequence of the mRNA template. During translation, the primary substrates, transfer RNAs, pass through binding sites formed between the two subunits. Multiple interactions between the ribosomal subunits, termed intersubunit bridges, keep the ribosome intact and at the same time govern dynamics that facilitate the various steps of translation such as transfer RNA-mRNA movement. Here, we review the molecular nature of these intersubunit bridges, how they change conformation during translation, and their functional roles in the process.
Topics: Protein Biosynthesis; RNA, Messenger; RNA, Transfer; Ribosomes
PubMed: 26880335
DOI: 10.1016/j.jmb.2016.02.009 -
Nucleic Acids Research Jan 2003The RECODE database is a compilation of translational recoding events (programmed ribosomal frameshifting, codon redefinition and translational bypass). The database...
The RECODE database is a compilation of translational recoding events (programmed ribosomal frameshifting, codon redefinition and translational bypass). The database provides information about the genes utilizing these events for their expression, recoding sites, stimulatory sequences and other relevant information. The Database is freely available at http://recode.genetics.utah.edu/.
Topics: Animals; Codon, Terminator; Databases, Genetic; Frameshifting, Ribosomal; Protein Biosynthesis; RNA, Messenger
PubMed: 12519954
DOI: 10.1093/nar/gkg024 -
Molecular Microbiology Dec 2019Translational control regulates the levels of protein synthesized from its transcript and is key for the rapid adjustment of gene expression in response to environmental... (Review)
Review
Translational control regulates the levels of protein synthesized from its transcript and is key for the rapid adjustment of gene expression in response to environmental stimuli. The regulation of translation is of special importance for malaria parasites, which pass through a complex life cycle that includes various replication phases in the different organs of the human and mosquito hosts and a sexual reproduction phase in the mosquito midgut. In particular, the quiescent transmission stages rely on translational control to rapidly adapt to the new environment, once they switch over from the human to the mosquito and vice versa. Three control mechanisms are currently proposed in Plasmodium, (1) global regulation that acts on the translation initiation complex; (2) mRNA-specific regulation, involving cis control elements, mRNA-binding proteins and translational repressors; and (3) induced mRNA decay by the Ccr4-Not and the RNA exosome complex. The main molecules controlling translation are highly conserved in malaria parasites and an increasing number of studies shed light on the interwoven pathways leading to the up or downregulation of protein synthesis in the diverse plasmodial stages. We here highlight recent findings on translational control during life cycle progression of Plasmodium and discuss the molecules involved in regulating protein synthesis.
Topics: Animals; Anopheles; Gene Expression Regulation; Humans; Malaria; Malaria, Falciparum; Parasites; Peptide Chain Initiation, Translational; Plasmodium; Plasmodium falciparum; Protein Biosynthesis; Protein Processing, Post-Translational; Protozoan Proteins; RNA, Messenger
PubMed: 31531994
DOI: 10.1111/mmi.14388 -
Nature Reviews. Genetics Oct 2009Errors in protein synthesis disrupt cellular fitness, cause disease phenotypes and shape gene and genome evolution. Experimental and theoretical results on this topic... (Review)
Review
Errors in protein synthesis disrupt cellular fitness, cause disease phenotypes and shape gene and genome evolution. Experimental and theoretical results on this topic have accumulated rapidly in disparate fields, such as neurobiology, protein biosynthesis and degradation and molecular evolution, but with limited communication among disciplines. Here, we review studies of error frequencies, the cellular and organismal consequences of errors and the attendant long-range evolutionary responses to errors. We emphasize major areas in which little is known, such as the failure rates of protein folding, in addition to areas in which technological innovations may enable imminent gains, such as the elucidation of translational missense error frequencies. Evolutionary responses to errors fall into two broad categories: adaptations that minimize errors and their attendant costs and adaptations that exploit errors for the organism's benefit.
Topics: Animals; Evolution, Molecular; Genetic Code; Humans; Protein Biosynthesis; Protein Folding; Transcription, Genetic
PubMed: 19763154
DOI: 10.1038/nrg2662 -
The Oncologist Feb 2015Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based... (Review)
Review
Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based targeting domain fused to a bacterial toxin payload for cell killing. Immunotoxins kill cells by inhibiting protein synthesis, a unique mechanism of action that is toxic to both dividing and nondividing cells. Recent advances in the design and administration of immunotoxins are overcoming historical challenges in the field, leading to renewed interest in these therapeutics.
Topics: Bacterial Toxins; Humans; Immunotoxins; Neoplasms; Protein Biosynthesis
PubMed: 25561510
DOI: 10.1634/theoncologist.2014-0358 -
Wiley Interdisciplinary Reviews. RNA 2013All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control... (Review)
Review
All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control transcription and activate second-messenger systems. More recent studies reveal that metabolites also affect post-transcriptional regulatory mechanisms. Here, we review the increasing number of connections between metabolism and post-transcriptional regulation in eukaryotic organisms. First, we present evidence that riboswitches, a common mechanism of metabolite sensing in bacteria, also function in eukaryotes. Next, we review an example of a double stranded RNA modifying enzyme that directly interacts with a metabolite, suggesting a link between RNA editing and metabolic state. Finally, we discuss work that shows some metabolic enzymes bind directly to RNA to affect mRNA stability or translation efficiency. These examples were discovered through gene-specific genetic, biochemical, and structural studies. A directed systems level approach will be necessary to determine whether they are anomalies of evolution or pioneer discoveries in what may be a broadly connected network of metabolism and post-transcriptional regulation.
Topics: Eukaryota; Gene Expression Regulation; Metabolic Networks and Pathways; Protein Biosynthesis; RNA Editing; RNA Stability
PubMed: 23653333
DOI: 10.1002/wrna.1167