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Journal of Genetics and Genomics = Yi... Apr 2024Messenger RNA (mRNA) translation consists of initiation, elongation, termination, and ribosome recycling, carried out by the translation machinery, primarily including... (Review)
Review
Messenger RNA (mRNA) translation consists of initiation, elongation, termination, and ribosome recycling, carried out by the translation machinery, primarily including tRNAs, ribosomes, and translation factors (TrFs). Translational regulators transduce signals of growth and development, as well as biotic and abiotic stresses, to the translation machinery, where global or selective translational control occurs to modulate mRNA translation efficiency (TrE). As the basis of translational control, the translation machinery directly determines the quality and quantity of newly synthesized peptides and, ultimately, the cellular adaption. Thus, regulating the availability of diverse machinery components is reviewed as the central strategy of translational control. We provide classical signaling pathways (e.g., integrated stress responses) and cellular behaviors (e.g., liquid-liquid phase separation) to exemplify this strategy within different physiological contexts, particularly during host-microbe interactions. With new technologies developed, further understanding this strategy will speed up translational medicine and translational agriculture.
Topics: Ribosomes; Proteins; RNA, Messenger; Peptides; Gene Expression Regulation; Protein Biosynthesis
PubMed: 37536497
DOI: 10.1016/j.jgg.2023.07.009 -
International Journal of Molecular... Nov 2021How can single cells without nervous systems perform complex behaviours such as habituation, associative learning and decision making, which are considered the hallmark... (Review)
Review
How can single cells without nervous systems perform complex behaviours such as habituation, associative learning and decision making, which are considered the hallmark of animals with a brain? Are there molecular systems that underlie cognitive properties equivalent to those of the brain? This review follows the development of the idea of molecular brains from Darwin's "root brain hypothesis", through bacterial chemotaxis, to the recent discovery of neuron-like r-protein networks in the ribosome. By combining a structural biology view with a Bayesian brain approach, this review explores the evolutionary labyrinth of information processing systems across scales. Ribosomal protein networks open a window into what were probably the earliest signalling systems to emerge before the radiation of the three kingdoms. While ribosomal networks are characterised by long-lasting interactions between their protein nodes, cell signalling networks are essentially based on transient interactions. As a corollary, while signals propagated in persistent networks may be ephemeral, networks whose interactions are transient constrain signals diffusing into the cytoplasm to be durable in time, such as post-translational modifications of proteins or second messenger synthesis. The duration and nature of the signals, in turn, implies different mechanisms for the integration of multiple signals and decision making. Evolution then reinvented networks with persistent interactions with the development of nervous systems in metazoans. Ribosomal protein networks and simple nervous systems display architectural and functional analogies whose comparison could suggest scale invariance in information processing. At the molecular level, the significant complexification of eukaryotic ribosomal protein networks is associated with a burst in the acquisition of new conserved aromatic amino acids. Knowing that aromatic residues play a critical role in allosteric receptors and channels, this observation suggests a general role of π systems and their interactions with charged amino acids in multiple signal integration and information processing. We think that these findings may provide the molecular basis for designing future computers with organic processors.
Topics: Animals; Bayes Theorem; Brain; Chemotaxis; Humans; Ribosomal Proteins; Ribosomes; Signal Transduction
PubMed: 34769300
DOI: 10.3390/ijms222111868 -
International Journal of Molecular... Mar 2023Ribosomal heterogeneity exists within cells and between different cell types, at specific developmental stages, and occurs in response to environmental stimuli. Mounting... (Review)
Review
Ribosomal heterogeneity exists within cells and between different cell types, at specific developmental stages, and occurs in response to environmental stimuli. Mounting evidence supports the existence of specialized ribosomes, or specific changes to the ribosome that regulate the translation of a specific group of transcripts. These alterations have been shown to affect the affinity of ribosomes for certain mRNAs or change the cotranslational folding of nascent polypeptides at the exit tunnel. The identification of specialized ribosomes requires evidence of the incorporation of different ribosomal proteins or of modifications to rRNA and/or protein that lead(s) to physiologically relevant changes in translation. In this review, we summarize ribosomal heterogeneity and specialization in mammals and discuss their relevance to several human diseases.
Topics: Animals; Humans; Protein Biosynthesis; Ribosomes; Ribosomal Proteins; RNA, Ribosomal; Peptides; Mammals
PubMed: 37047306
DOI: 10.3390/ijms24076334 -
Nucleic Acids Research Feb 2020During protein synthesis, translating ribosomes encounter many challenges imposed by various types of defective mRNAs that can lead to reduced cellular fitness and, in... (Review)
Review
During protein synthesis, translating ribosomes encounter many challenges imposed by various types of defective mRNAs that can lead to reduced cellular fitness and, in some cases, even threaten cell viability. Aberrant translation leads to activation of one of several quality control pathways depending on the nature of the problem. These pathways promote the degradation of the problematic mRNA as well as the incomplete translation product, the nascent polypeptide chain. Many of these quality control systems feature critical roles for specialized regulatory factors that work in concert with conventional factors. This review focuses on the mechanisms used by these quality control pathways to recognize aberrant ribosome stalling and discusses the conservation of these systems.
Topics: Peptides; Proteasome Endopeptidase Complex; Protein Biosynthesis; RNA Stability; RNA, Messenger; RNA, Ribosomal; Ribosomes; Ubiquitination
PubMed: 31950154
DOI: 10.1093/nar/gkz1201 -
Cells Feb 2020Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in... (Review)
Review
Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries. Although chromatin remodeling and mRNA expression have been extensively studied in stem cells, accumulating evidence suggests that stem cell transcriptomes and proteomes are poorly correlated and that stem cell properties require finely tuned protein synthesis. In addition, many studies have shown that the biogenesis of the translation machinery, the ribosome, is decisive for sustaining ESC and ASC properties. Therefore, these observations emphasize the importance of translational control in stem cell homeostasis and fate decisions. In this review, we will provide the most recent literature describing how ribosome biogenesis and translational control regulate stem cell functions and are crucial for accommodating proteome remodeling in response to changes in stem cell fate.
Topics: Adult Stem Cells; Animals; Cell Differentiation; Embryonic Stem Cells; Homeostasis; Humans; Mice; Protein Biosynthesis; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 32098201
DOI: 10.3390/cells9020497 -
The Journal of Cell Biology Jun 2020Translation control is critical to regulate protein expression. By directly adjusting protein levels, cells can quickly respond to dynamic transitions during stem cell... (Review)
Review
Translation control is critical to regulate protein expression. By directly adjusting protein levels, cells can quickly respond to dynamic transitions during stem cell differentiation and embryonic development. Ribosomes are multisubunit cellular assemblies that mediate translation. Previously seen as invariant machines with the same composition of components in all conditions, recent studies indicate that ribosomes are heterogeneous and that different ribosome types can preferentially translate specific subsets of mRNAs. Such heterogeneity and specialized translation functions are very important in stem cells and development, as they allow cells to quickly respond to stimuli through direct changes of protein abundance. In this review, we discuss ribosome heterogeneity that arises from multiple features of rRNAs, including rRNA variants and rRNA modifications, and ribosomal proteins, including their stoichiometry, compositions, paralogues, and posttranslational modifications. We also discuss alterations of ribosome-associated proteins (RAPs), with a particular focus on their consequent specialized translational control in stem cells and development.
Topics: Cell Differentiation; Growth and Development; Humans; Protein Biosynthesis; Protein Processing, Post-Translational; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes; Stem Cells
PubMed: 32330234
DOI: 10.1083/jcb.202001108 -
Cancer Science May 2023Ribosome biogenesis in the nucleolus is an important process that consumes 80% of a cell's intracellular energy supply. Disruption of this process results in nucleolar... (Review)
Review
Ribosome biogenesis in the nucleolus is an important process that consumes 80% of a cell's intracellular energy supply. Disruption of this process results in nucleolar stress, triggering the activation of molecular systems that respond to this stress to maintain homeostasis. Although nucleolar stress was originally thought to be caused solely by abnormalities of ribosomal RNA (rRNA) and ribosomal proteins (RPs), an accumulating body of more current evidence suggests that many other factors, including the DNA damage response and oncogenic stress, are also involved in nucleolar stress response signaling. Cells reacting to nucleolar stress undergo cell cycle arrest or programmed death, mainly driven by activation of the tumor suppressor p53. This observation has nominated nucleolar stress as a promising target for cancer therapy. However, paradoxically, some RP mutations have also been implicated in cancer initiation and progression, necessitating caution. In this article, we summarize recent findings on the molecular mechanisms of nucleolar stress and the human ribosomal diseases and cancers that arise in its wake.
Topics: Humans; Ribosomal Proteins; Ribosomes; Tumor Suppressor Protein p53; RNA, Ribosomal; Cell Cycle Checkpoints; Neoplasms
PubMed: 36762786
DOI: 10.1111/cas.15755 -
Seminars in Cell & Developmental Biology Feb 2024Cells entrust ribosomes with the critical task of identifying problematic mRNAs and facilitating their degradation. Ribosomes must communicate when they encounter and... (Review)
Review
Cells entrust ribosomes with the critical task of identifying problematic mRNAs and facilitating their degradation. Ribosomes must communicate when they encounter and stall on an aberrant mRNA, lest they expose the cell to toxic and disease-causing proteins, or they jeopardize ribosome homeostasis and cellular translation. In recent years, ribosomal ubiquitination has emerged as a central signaling step in this process, and proteomic studies across labs and experimental systems show a myriad of ubiquitination sites throughout the ribosome. Work from many labs zeroed in on ubiquitination in one region of the small ribosomal subunit as being functionally significant, with the balance and exact ubiquitination sites determined by stall type, E3 ubiquitin ligases, and deubiquitinases. This review discusses the current literature surrounding ribosomal ubiquitination during translational stress and considers its role in committing translational complexes to decay.
Topics: Ubiquitin; Proteomics; Saccharomyces cerevisiae; Ribosomes; Ubiquitination; RNA, Messenger; Protein Biosynthesis
PubMed: 36963992
DOI: 10.1016/j.semcdb.2023.03.009 -
Advanced Science (Weinheim,... Jul 2023KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the...
KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX-5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition.
Topics: Humans; Animals; Mice; Leukemia, Myeloid, Acute; Genes, Tumor Suppressor; TOR Serine-Threonine Kinases; RNA, Small Interfering; Ribosomes
PubMed: 37142882
DOI: 10.1002/advs.202206098 -
RNA Biology Oct 2021Ribosomes are essential nanomachines responsible for all protein production in cells. Ribosome biogenesis and function are energy costly processes, they are tightly... (Review)
Review
Ribosomes are essential nanomachines responsible for all protein production in cells. Ribosome biogenesis and function are energy costly processes, they are tightly regulated to match cellular needs. In cancer, major pathways that control ribosome biogenesis and function are often deregulated to ensure cell survival and to accommodate the continuous proliferation of tumour cells. Ribosomal RNAs (rRNAs) are abundantly modified with 2'-O-methylation (Nm, ribomethylation) being one of the most common modifications. In eukaryotic ribosomes, ribomethylation is performed by the methyltransferase Fibrillarin guided by box C/D small nucleolar RNAs (snoRNAs). Accumulating evidences indicate that snoRNA expression and ribosome methylation profiles are altered in cancer. Here we review our current knowledge on differential snoRNA expression and rRNA 2'-O methylation in the context of human malignancies, and discuss the consequences and opportunities for cancer diagnostics, prognostics, and therapeutics.
Topics: Animals; Humans; Methylation; Neoplasms; RNA Processing, Post-Transcriptional; RNA, Ribosomal; RNA, Small Nucleolar; Ribosomes
PubMed: 34775914
DOI: 10.1080/15476286.2021.1991167