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Oncogene Nov 2021A key characteristic of cancer cells is their increased proliferative capacity, which requires elevated levels of protein synthesis. The process of protein synthesis... (Review)
Review
A key characteristic of cancer cells is their increased proliferative capacity, which requires elevated levels of protein synthesis. The process of protein synthesis involves the translation of codons within the mRNA coding sequence into a string of amino acids to form a polypeptide chain. As most amino acids are encoded by multiple codons, the nucleotide sequence of a coding region can vary dramatically without altering the polypeptide sequence of the encoded protein. Although mutations that do not alter the final amino acid sequence are often thought of as silent/synonymous, these can still have dramatic effects on protein output. Because each codon has a distinct translation elongation rate and can differentially impact mRNA stability, each codon has a different degree of 'optimality' for protein synthesis. Recent data demonstrates that the codon preference of a transcriptome matches the abundance of tRNAs within the cell and that this supply and demand between tRNAs and mRNAs varies between different cell types. The largest observed distinction is between mRNAs encoding proteins associated with proliferation or differentiation. Nevertheless, precisely how codon optimality and tRNA expression levels regulate cell fate decisions and their role in malignancy is not fully understood. This review describes the current mechanistic understanding on codon optimality, its role in malignancy and discusses the potential to target codon optimality therapeutically in the context of cancer.
Topics: Codon; Humans; Mutation; Neoplasms; Protein Biosynthesis; RNA Stability; RNA, Messenger; RNA, Transfer
PubMed: 34584217
DOI: 10.1038/s41388-021-02022-x -
Current Opinion in Chemical Biology Feb 2016Chemical modifications in cellular RNA are diverse and abundant. Commonly found in ribosomal RNA (rRNA), transfer RNA (tRNA), long-noncoding RNA (lncRNA), and small... (Review)
Review
Chemical modifications in cellular RNA are diverse and abundant. Commonly found in ribosomal RNA (rRNA), transfer RNA (tRNA), long-noncoding RNA (lncRNA), and small nuclear (snRNA), these components play various structural and functional roles. Until recently, the roles of chemical modifications within messenger RNA (mRNA) have been understudied. Recent maps of several mRNA modifications have suggested regulatory functions for these marks. This review summarizes recent advances in identifying and understanding biological roles of posttranscriptional mRNA modification, or 'RNA epigenetics', with an emphasis on the most common internal modification of eukaryotic mRNA, N(6)-methyladenosine (m(6)A). We also discuss YTH proteins as direct mediators of m(6)A function and the emerging role of this mark in a new layer of gene expression regulation.
Topics: Animals; Epigenesis, Genetic; Humans; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 26625014
DOI: 10.1016/j.cbpa.2015.10.024 -
International Journal of Molecular... May 2020Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode... (Review)
Review
Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.
Topics: Acute Disease; Animals; Gene Expression Regulation, Leukemic; Humans; Leukemia; Nucleic Acid Conformation; Protein Binding; Protein Domains; RNA, Messenger; RNA-Binding Proteins
PubMed: 32408494
DOI: 10.3390/ijms21103409 -
Molecular Cell Jul 2022Stress-induced condensation of mRNA and protein into massive cytosolic clusters is conserved across eukaryotes. Known as stress granules when visible by imaging, these... (Review)
Review
Stress-induced condensation of mRNA and protein into massive cytosolic clusters is conserved across eukaryotes. Known as stress granules when visible by imaging, these structures remarkably have no broadly accepted biological function, mechanism of formation or dispersal, or even molecular composition. As part of a larger surge of interest in biomolecular condensation, studies of stress granules and related RNA/protein condensates have increasingly probed the biochemical underpinnings of condensation. Here, we review open questions and recent advances, including the stages from initial condensate formation to accumulation in mature stress granules, mechanisms by which stress-induced condensates form and dissolve, and surprising twists in understanding the RNA components of stress granules and their role in condensation. We outline grand challenges in understanding stress-induced RNA condensation, centering on the unique and substantial barriers in the molecular study of cellular structures, such as stress granules, for which no biological function has been firmly established.
Topics: RNA; RNA, Messenger; Stress Granules
PubMed: 35662398
DOI: 10.1016/j.molcel.2022.05.014 -
Biochimica Et Biophysica Acta. Gene... Mar 2019
Review
Topics: Adenine; Animals; Humans; Protein Biosynthesis; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 30342175
DOI: 10.1016/j.bbagrm.2018.10.006 -
Biomolecules Jan 2016RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA... (Review)
Review
RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA localization, mRNA turn-over as well as translation. Given their diverse functions, cells express a variety of RNA-binding proteins, which play important roles in the pathologies of a number of diseases. In this review we focus on the effect of alcohol on different RNA-binding proteins and their possible contribution to alcohol-related disorders, and discuss the role of these proteins in the development of neurological diseases and cancer. We further discuss the conventional methods and newer techniques that are employed to identify RNA-binding proteins.
Topics: Alcohol-Related Disorders; Alcohols; Binding Sites; Gene Expression Regulation; Humans; Neoplasms; Nervous System Diseases; RNA Splicing; RNA Stability; RNA, Messenger; RNA-Binding Proteins
PubMed: 26751491
DOI: 10.3390/biom6010004 -
Critical Reviews in Biochemistry and... Apr 2017Protein translation is one of the most energetically demanding processes for a cell to undertake. Changes in the nutrient environment may result in conditions that... (Review)
Review
Protein translation is one of the most energetically demanding processes for a cell to undertake. Changes in the nutrient environment may result in conditions that cannot support the rates of translation required for cell proliferation. As such, a cell must monitor its metabolic state to determine which mRNAs to translate into protein. How the various RNA species that participate in translation might relay information about metabolic state to regulate this process is not well understood. In this review, we discuss emerging examples of the influence of metabolism on aspects of RNA biology. We discuss how metabolic state impacts the localization and fate of different RNA species, as well as how nutrient cues can impact post-transcriptional modifications of RNA to regulate their functions in the control of translation.
Topics: Animals; Gene Expression Regulation; Humans; Metabolic Networks and Pathways; Nutritional Physiological Phenomena; Protein Biosynthesis; Proteins; RNA; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 28152618
DOI: 10.1080/10409238.2017.1283294 -
Cold Spring Harbor Perspectives in... May 2018RNA decay plays a major role in regulating gene expression and is tightly networked with other aspects of gene expression to effectively coordinate post-transcriptional... (Review)
Review
RNA decay plays a major role in regulating gene expression and is tightly networked with other aspects of gene expression to effectively coordinate post-transcriptional regulation. The goal of this work is to provide an overview of the major factors and pathways of general messenger RNA (mRNA) decay in eukaryotic cells, and then discuss the effective interplay of this cytoplasmic process with the protein synthesis machinery. Given the transcript-specific and fluid nature of mRNA stability in response to changing cellular conditions, understanding the fundamental networking between RNA decay and translation will provide a foundation for a complete mechanistic understanding of this important aspect of cell biology.
Topics: Eukaryota; Gene Expression Regulation; Models, Genetic; Protein Biosynthesis; RNA Stability; RNA, Messenger
PubMed: 29311343
DOI: 10.1101/cshperspect.a032839 -
Annals of the New York Academy of... Jul 2019In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. This key process is universally conserved and... (Review)
Review
In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. This key process is universally conserved and plays a crucial role in the viability and virulence of all bacteria. It is performed by transfer-messenger RNA (tmRNA) and its protein partner small protein B (SmpB). Here, we show that tmRNA is a key molecule that could have given birth to modern protein synthesis. The traces of an ancient RNA world persist in the structure of modern tmRNA, suggesting its old origins. Therefore, since it has both tRNA and mRNA functions, tmRNA could be the missing link that allowed modern genetic code to be read by the ribosome.
Topics: Animals; Humans; Protein Biosynthesis; Protein Structure, Secondary; RNA, Bacterial; RNA, Messenger; RNA, Transfer
PubMed: 30815901
DOI: 10.1111/nyas.14035 -
Journal of Molecular Biology Jul 2017G-quadruplexes (G4s) are extremely stable DNA or RNA secondary structures formed by sequences rich in guanine. These structures are implicated in many essential cellular... (Review)
Review
G-quadruplexes (G4s) are extremely stable DNA or RNA secondary structures formed by sequences rich in guanine. These structures are implicated in many essential cellular processes, and the number of biological functions attributed to them continues to grow. While DNA G4s are well understood on structural and, to some extent, functional levels, RNA G4s and their functions have received less attention. The presence of bona fide RNA G4s in cells has long been a matter of debate. The development of G4-specific antibodies and ligands hinted on their presence in vivo, but recent advances in RNA sequencing coupled with chemical footprinting suggested the opposite. In this review, we will critically discuss the biology of RNA G4s focusing on the molecular mechanisms underlying their proposed functions.
Topics: G-Quadruplexes; Gene Expression Regulation; Protein Biosynthesis; RNA, Messenger; Transcription, Genetic
PubMed: 28554731
DOI: 10.1016/j.jmb.2017.05.017