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Cell Sep 2019The RNA exosome is a 3' to 5' ribonuclease that plays a fundamental role in maturation, quality control, and turnover of nearly all types of RNA produced in eukaryotic...
The RNA exosome is a 3' to 5' ribonuclease that plays a fundamental role in maturation, quality control, and turnover of nearly all types of RNA produced in eukaryotic cells. Here, we present an overview of the structure, composition, and functions of the RNA exosome, including various cytoplasmic and nuclear exosome co-factors and associated protein complexes. To view this SnapShot, open or download the PDF.
Topics: Cell Nucleus; Cytoplasm; Exosome Multienzyme Ribonuclease Complex; Exosomes; Humans; RNA Helicases; RNA Stability; RNA, Messenger; RNA, Ribosomal
PubMed: 31539497
DOI: 10.1016/j.cell.2019.09.005 -
The Journal of Clinical Investigation Nov 2023Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid...
Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3βHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3βHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3βHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.
Topics: Humans; Male; Androgen Antagonists; Androgens; DNA; Genotype; Hydroxysteroid Dehydrogenases; Multienzyme Complexes; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 37966114
DOI: 10.1172/JCI165718 -
Gastroenterology Jul 2021Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2...
BACKGROUND & AIMS
Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study was to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis.
METHODS
Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2) were created and subjected to dextran sodium sulfate-induced colitis and colonic carcinogenesis induced by a combined treatment of azoxymethane and dextran sodium sulfate or azoxymethane alone.
RESULTS
The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2 mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2 mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids, including the Farnesoid X receptor antagonist bile acid tauro-β-muricholic acid, and deficiency in the formation of bile acid sulfates in the colon of Papss2 mice.
CONCLUSIONS
We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.
Topics: Animals; Bile Acids and Salts; Colitis; Colitis-Associated Neoplasms; Colon; Databases, Genetic; Disease Models, Animal; Humans; Intestinal Mucosa; Metabolome; Metabolomics; Mice, Inbred C57BL; Mice, Knockout; Mucins; Multienzyme Complexes; Prognosis; Receptors, Cytoplasmic and Nuclear; Sulfate Adenylyltransferase; Mice
PubMed: 33819483
DOI: 10.1053/j.gastro.2021.03.048 -
Molecules (Basel, Switzerland) Sep 2022Cells have developed intelligent systems to implement the complex and efficient enzyme cascade reactions via the strategies of organelles, bacterial microcompartments... (Review)
Review
Cells have developed intelligent systems to implement the complex and efficient enzyme cascade reactions via the strategies of organelles, bacterial microcompartments and enzyme complexes. The scaffolds such as the membrane or protein in the cell are believed to assist the co-localization of enzymes and enhance the enzymatic reactions. Inspired by nature, enzymes have been located on a wide variety of carriers, among which DNA scaffolds attract great interest for their programmability and addressability. Integrating these properties with the versatile DNA-protein conjugation methods enables the spatial arrangement of enzymes on the DNA scaffold with precise control over the interenzyme distance and enzyme stoichiometry. In this review, we survey the reactions of a single type of enzyme on the DNA scaffold and discuss the proposed mechanisms for the catalytic enhancement of DNA-scaffolded enzymes. We also review the current progress of enzyme cascade reactions on the DNA scaffold and discuss the factors enhancing the enzyme cascade reaction efficiency. This review highlights the mechanistic aspects for the modulation of enzymatic reactions on the DNA scaffold.
Topics: Catalysis; DNA; Multienzyme Complexes; Proteins
PubMed: 36234845
DOI: 10.3390/molecules27196309 -
Journal of Natural Medicines Jun 2021It has been proposed that biosyntheses of many natural products involve pericyclic reactions, including Diels-Alder (DA) reaction. However, only a small set of enzymes... (Review)
Review
It has been proposed that biosyntheses of many natural products involve pericyclic reactions, including Diels-Alder (DA) reaction. However, only a small set of enzymes have been proposed to catalyze pericyclic reactions. Most surprisingly, there has been no formal identification of natural enzymes that can be defined to catalyze DA reactions (DAases), despite the wide application of the reaction in chemical syntheses of complex organic compounds. However, recent studies began to accumulate a growing body of evidence that supports the notion that enzymes that formally catalyze DA reactions, in fact exist. In this review, I will begin by describing a short history behind the discovery and characterization of macrophomate synthase, one of the earliest enzymes that was proposed to catalyze an intermolecular DA reaction during the biosynthesis of a substituted benzoic acid in a phytopathogenic fungus Macrophoma commelinae. Then, I will discuss representative enzymes that have been chemically authenticated to catalyze DA reactions, with emphasis on more recent discoveries of DAases involved mainly in fungal secondary metabolite biosynthesis except for one example from a marine streptomycete. The current success in identification of a series of DAases and enzymes that catalyze other pericyclic reactions owes to the combined efforts from both the experimental and theoretical approaches in discovering natural products. Such efforts typically involve identifying the chemical features derived from cycloaddition reactions, isolating the biosynthetic genes that encode enzymes that generate such chemical features and deciphering the reaction mechanisms for the enzyme-catalyzed pericyclic reactions.
Topics: Ascomycota; Biological Products; Cycloaddition Reaction; Multienzyme Complexes; Secondary Metabolism
PubMed: 33683566
DOI: 10.1007/s11418-021-01502-4 -
The Plant Cell Mar 2022RNA exosome complexes provide the main 3'-5'-exoribonuclease activities in eukaryotic cells and contribute to the maturation and degradation of virtually all types of... (Review)
Review
RNA exosome complexes provide the main 3'-5'-exoribonuclease activities in eukaryotic cells and contribute to the maturation and degradation of virtually all types of RNA. RNA exosomes consist of a conserved core complex that associates with exoribonucleases and with multimeric cofactors that recruit the enzyme to its RNA targets. Despite an overall high level of structural and functional conservation, the enzymatic activities and compositions of exosome complexes and their cofactor modules differ among eukaryotes. This review highlights unique features of plant exosome complexes, such as the phosphorolytic activity of the core complex, and discusses the exosome cofactors that operate in plants and are dedicated to the maturation of ribosomal RNA, the elimination of spurious, misprocessed, and superfluous transcripts, or the removal of mRNAs cleaved by the RNA-induced silencing complex and other mRNAs prone to undergo silencing.
Topics: Exoribonucleases; Exosome Multienzyme Ribonuclease Complex; Exosomes; RNA; RNA Stability; Saccharomyces cerevisiae Proteins
PubMed: 34954803
DOI: 10.1093/plcell/koab310 -
International Journal of Molecular... Nov 2021The members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family play vital roles in multiple biological processes, including DNA damage response,... (Review)
Review
The members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family play vital roles in multiple biological processes, including DNA damage response, metabolism, cell growth, mRNA decay, and transcription. TRRAP, as the only member lacking the enzymatic activity in this family, is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors. TRRAP has been demonstrated to regulate various cellular functions in cell cycle progression, cell stemness maintenance and differentiation, as well as neural homeostasis. TRRAP is known to be an important orchestrator of many molecular machineries in gene transcription by modulating the activity of some key transcription factors, including E2F1, c-Myc, p53, and recently, Sp1. This review summarizes the biological and biochemical studies on the action mode of TRRAP together with the transcription factors, focusing on how TRRAP-HAT mediates the transactivation of Sp1-governing biological processes, including neurodegeneration.
Topics: Adaptor Proteins, Signal Transducing; Animals; E2F1 Transcription Factor; Gene Expression Regulation; Histone Acetyltransferases; Humans; Multienzyme Complexes; Neurodegenerative Diseases; Neurogenesis; Nuclear Proteins; Protein Binding; Proto-Oncogene Proteins c-myc; Signal Transduction; Sp1 Transcription Factor; Transcription, Genetic; Tumor Suppressor Protein p53
PubMed: 34830324
DOI: 10.3390/ijms222212445 -
Urology Nov 2020Dihydrotestosterone synthesis in prostate cancer from adrenal DHEA/DHEA-sulfate requires enzymatic conversion in tumor tissues. 3β-hydroxysteroid dehydrogenase-1 is an... (Review)
Review
Dihydrotestosterone synthesis in prostate cancer from adrenal DHEA/DHEA-sulfate requires enzymatic conversion in tumor tissues. 3β-hydroxysteroid dehydrogenase-1 is an absolutely necessary enzyme for such dihydrotestosterone synthesis and is encoded by the gene HSD3B1 which comes in 2 functional inherited forms described in 2013. The adrenal-permissive HSD3B1(1245C) allele allows for rapid dihydrotestosterone synthesis. The adrenal-restrictive HSD3B1(1245A) allele limits androgen synthesis. Studies from multiple cohorts show that adrenal-permissive allele inheritance confers worse outcomes and shorter survival after castration in low-volume prostate cancer and poor outcomes after abiraterone or enzalutamide treatment for castration-resistant prostate cancer. Here, we review the clinical data and implications.
Topics: Androgen Antagonists; Germ Cells; Humans; Male; Multienzyme Complexes; Progesterone Reductase; Prostatic Neoplasms; Steroid Isomerases; Treatment Outcome
PubMed: 32866512
DOI: 10.1016/j.urology.2020.08.028 -
Chemical Reviews Dec 2019Assembly-line polyketide synthases (PKSs) are among the most complex protein machineries known in nature, responsible for the biosynthesis of numerous compounds used in... (Review)
Review
Assembly-line polyketide synthases (PKSs) are among the most complex protein machineries known in nature, responsible for the biosynthesis of numerous compounds used in the clinic. Their present-day diversity is the result of an evolutionary path that has involved the emergence of a multimodular architecture and further diversification of assembly-line PKSs. In this review, we provide an overview of previous studies that investigated PKS evolution and propose a model that challenges the currently prevailing view that gene duplication has played a major role in the emergence of multimodularity. We also analyze the ensemble of orphan PKS clusters sequenced so far to evaluate how large the entire diversity of assembly-line PKS clusters and their chemical products could be. Finally, we examine the existing techniques to access the natural PKS diversity in natural and heterologous hosts and describe approaches to further expand this diversity through engineering.
Topics: Catalysis; Evolution, Molecular; Models, Genetic; Polyketide Synthases; Protein Domains
PubMed: 31838842
DOI: 10.1021/acs.chemrev.9b00525 -
Biochimica Et Biophysica Acta.... Nov 2019Photosynthetic pigment-protein complexes (PPCs) accomplish light-energy capture and photochemistry in natural photosynthesis. In this review, we examine three pigment... (Review)
Review
Photosynthetic pigment-protein complexes (PPCs) accomplish light-energy capture and photochemistry in natural photosynthesis. In this review, we examine three pigment protein complexes in oxygenic photosynthesis: light-harvesting antenna complexes and two reaction centers: Photosystem II (PSII), and Photosystem I (PSI). Recent technological developments promise unprecedented insights into how these multi-component protein complexes are assembled into higher order structures and thereby execute their function. Furthermore, the interfacial domain between light-harvesting antenna complexes and PSII, especially the potential roles of the structural loops from CP29 and the PB-loop of ApcE in higher plant and cyanobacteria, respectively, are discussed. It is emphasized that the structural nuances are required for the structural dynamics and consequently for functional regulation in response to an ever-changing and challenging environment.
Topics: Cyanobacteria; Light-Harvesting Protein Complexes; Photosynthesis; Photosystem I Protein Complex; Photosystem II Protein Complex; Plants; Rhodophyta
PubMed: 31518567
DOI: 10.1016/j.bbabio.2019.148079