scholarly journals Polyamines as Quality Control Metabolites Operating at the Post-Transcriptional Level

Plants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 109 ◽  
Author(s):  
Laetitia Poidevin ◽  
Dilek Unal ◽  
Borja Belda-Palazón ◽  
Alejandro Ferrando
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
Control Mechanisms ◽  
Physiological Functions ◽  
Nonsense Mediated Decay ◽  
Stop Codons ◽  
Ribosome Stalling ◽  
Molecular Functions

Plant polyamines (PAs) have been assigned a large number of physiological functions with unknown molecular mechanisms in many cases. Among the most abundant and studied polyamines, two of them, namely spermidine (Spd) and thermospermine (Tspm), share some molecular functions related to quality control pathways for tightly regulated mRNAs at the level of translation. In this review, we focus on the roles of Tspm and Spd to facilitate the translation of mRNAs containing upstream ORFs (uORFs), premature stop codons, and ribosome stalling sequences that may block translation, thus preventing their degradation by quality control mechanisms such as the nonsense-mediated decay pathway and possible interactions with other mRNA quality surveillance pathways.

scholarly journals Nuclear mRNA Quality Control and Cytoplasmic NMD Are Linked by the Guard Proteins Gbp2 and Hrb1

2021 ◽  
Vol 22 (20) ◽  
pp. 11275
Author(s):  
Yen-Yun Lu ◽  
Heike Krebber
Keyword(s):  
Quality Control ◽  
Control Function ◽  
Stop Codon ◽  
Model Organism ◽  
Rna Degradation ◽  
Mrna Splicing ◽  
Open Reading Frames ◽  
Control Mechanisms ◽  
Nonsense Mediated Decay ◽  
Control Factors

Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) at exon-exon boundaries. This “memory” of splicing events is important for the ribosome, which translates the RNAs in the cytoplasm. In case a stop codon was detected before an EJC, translation is blocked and the RNA is eliminated by the nonsense-mediated decay (NMD). In the model organism Saccharomyces cerevisiae, two guard proteins, Gbp2 and Hrb1, have been identified as nuclear quality control factors for splicing. In their absence, intron-containing mRNAs leak into the cytoplasm. Their presence retains transcripts until the process is completed and they release the mRNAs by recruitment of the export factor Mex67. On transcripts that experience splicing problems, these guard proteins recruit the nuclear RNA degradation machinery. Interestingly, they continue their quality control function on exported transcripts. They support NMD by inhibiting translation and recruiting the cytoplasmic degradation factors. In this way, they link the nuclear and cytoplasmic quality control systems. These discoveries are also intriguing for humans, as homologues of these guard proteins are present also in multicellular organisms. Here, we provide an overview of the quality control mechanisms of pre-mRNA splicing, and present Gbp2 and Hrb1, as well as their human counterparts, as important players in these pathways.

scholarly journals Structural and functional analysis of the three MIF4G domains of nonsense-mediated decay factor UPF2

2013 ◽  
Vol 42 (4) ◽  
pp. 2673-2686 ◽  
Author(s):  
Marcello Clerici ◽  
Aurélien Deniaud ◽  
Volker Boehm ◽  
Niels H. Gehring ◽  
Christiane Schaffitzel ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Quality Control ◽  
Binding Site ◽  
Crystal Structures ◽  
Binding Region ◽  
Nonsense Mediated Decay ◽  
Stop Codons ◽  
Decay Factor

Abstract Nonsense-mediated decay (NMD) is a eukaryotic quality control pathway, involving conserved proteins UPF1, UPF2 and UPF3b, which detects and degrades mRNAs with premature stop codons. Human UPF2 comprises three tandem MIF4G domains and a C-terminal UPF1 binding region. MIF4G-3 binds UPF3b, but the specific functions of MIF4G-1 and MIF4G-2 are unknown. Crystal structures show that both MIF4G-1 and MIF4G-2 contain N-terminal capping helices essential for stabilization of the 10-helix MIF4G core and that MIF4G-2 interacts with MIF4G-3, forming a rigid assembly. The UPF2/UPF3b/SMG1 complex is thought to activate the kinase SMG1 to phosphorylate UPF1 in vivo. We identify MIF4G-3 as the binding site and in vitro substrate of SMG1 kinase and show that a ternary UPF2 MIF4G-3/UPF3b/SMG1 complex can form in vitro. Whereas in vivo complementation assays show that MIF4G-1 and MIF4G-2 are essential for NMD, tethering assays reveal that UPF2 truncated to only MIF4G-3 and the UPF1-binding region can still partially accomplish NMD. Thus UPF2 MIF4G-1 and MIF4G-2 appear to have a crucial scaffolding role, while MIF4G-3 is the key module required for triggering NMD.

scholarly journals The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

2009 ◽  
Vol 20 (15) ◽  
pp. 3459-3470 ◽  
Author(s):  
Viktoria Hessle ◽  
Petra Björk ◽  
Marcus Sokolowski ◽  
Ernesto González de Valdivia ◽  
Rebecca Silverstein ◽  
...  
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Mechanistic Model ◽  
Model Systems ◽  
Control Mechanisms ◽  
Hnrnp Proteins ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Transcription Sites ◽  
Mrna Binding

Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.

scholarly journals Molecular Mechanisms and Regulation of Mammalian Mitophagy

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 38
Author(s):  
Vinay Choubey ◽  
Akbar Zeb ◽  
Allen Kaasik
Keyword(s):  
Quality Control ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Stress Protein ◽  
Antioxidant Defenses ◽  
Control Mechanisms ◽  
Mitochondrial Dna Damage ◽  
Cellular Environment ◽  
Rigorous Research ◽  
Functional Versatility

Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.

scholarly journals The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation

2019 ◽  
Author(s):  
Andrea Hildebrandt ◽  
Mirko Brüggemann ◽  
Susan Boerner ◽  
Cornelia Rücklé ◽  
Jan Bernhard Heidelberger ◽  
...  
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Rna Binding ◽  
Mrna Level ◽  
Ring Finger ◽  
Common Source ◽  
Control Mechanisms ◽  
Functional Protein ◽  
Ribosome Stalling ◽  
Translational Regulators

AbstractCells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via the ribosome-associated quality control (RQC). Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at poly(A) sequences during RQC. We show that MKRN1 interacts with the cytoplasmic poly(A)-binding protein (PABP) and is positioned upstream of poly(A) tails in mRNAs. Ubiquitin remnant profiling uncovers PABP and ribosomal protein RPS10, as well as additional translational regulators as main ubiquitylation substrates of MKRN1. We propose that MKRN1 serves as a first line of poly(A) recognition at the mRNA level to prevent production of erroneous proteins, thus maintaining proteome integrity.

scholarly journals APE1/Ref-1 Interacts with NPM1 within Nucleoli and Plays a Role in the rRNA Quality Control Process

2009 ◽  
Vol 29 (7) ◽  
pp. 1834-1854 ◽  
Author(s):  
Carlo Vascotto ◽  
Damiano Fantini ◽  
Milena Romanello ◽  
Laura Cesaratto ◽  
Marta Deganuto ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rrna Synthesis ◽  
Control Mechanisms ◽  
Endonuclease Activity ◽  
Proteomic Approach ◽  
Quality Control Process

ABSTRACT APE1/Ref-1 (hereafter, APE1), a DNA repair enzyme and a transcriptional coactivator, is a vital protein in mammals. Its role in controlling cell growth and the molecular mechanisms that fine-tune its different cellular functions are still not known. By an unbiased proteomic approach, we have identified and characterized several novel APE1 partners which, unexpectedly, include a number of proteins involved in ribosome biogenesis and RNA processing. In particular, a novel interaction between nucleophosmin (NPM1) and APE1 was characterized. We observed that the 33 N-terminal residues of APE1 are required for stable interaction with the NPM1 oligomerization domain. As a consequence of the interaction with NPM1 and RNA, APE1 is localized within the nucleolus and this localization depends on cell cycle and active rRNA transcription. NPM1 stimulates APE1 endonuclease activity on abasic double-stranded DNA (dsDNA) but decreases APE1 endonuclease activity on abasic single-stranded RNA (ssRNA) by masking the N-terminal region of APE1 required for stable RNA binding. In APE1-knocked-down cells, pre-rRNA synthesis and rRNA processing were not affected but inability to remove 8-hydroxyguanine-containing rRNA upon oxidative stress, impaired translation, lower intracellular protein content, and decreased cell growth rate were found. Our data demonstrate that APE1 affects cell growth by directly acting on RNA quality control mechanisms, thus affecting gene expression through posttranscriptional mechanisms.

scholarly journals The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Andrea Hildebrandt ◽  
Mirko Brüggemann ◽  
Cornelia Rücklé ◽  
Susan Boerner ◽  
Jan B. Heidelberger ◽  
...  
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Rna Binding ◽  
Ring Finger ◽  
Common Source ◽  
Control Mechanisms ◽  
Dependent Manner ◽  
Functional Protein ◽  
Ribosome Stalling

Abstract Background Cells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via ribosome-associated quality control. Results Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at poly(A) sequences during ribosome-associated quality control. We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1. Conclusions We propose that MKRN1 mediates the recognition of poly(A) tails to prevent the production of erroneous proteins from prematurely polyadenylated transcripts, thereby maintaining proteome integrity.

scholarly journals Mitophagy Eliminates the Accumulation of SARM1 on the Mitochondria, Alleviating Programmed Axon Death in Acrylamide Neuropathy

2022 ◽  
Author(s):  
Shuai Wang ◽  
Hui Yong ◽  
Cuiqin Zhang ◽  
Kang Kang ◽  
Mingxue Song ◽  
...  
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Biological Significance ◽  
Control Mechanisms ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Mitochondrial Localization ◽  
Mitochondrial Quality Control ◽  
Axon Loss

Abstract Sterile-α and toll/interleukin 1 receptor motif containing protein 1 (SARM1) is the central executioner of programmed axon death (Wallerian degeneration). Although it has been confirmed to have a mitochondrial targeting sequence and can bind to and stabilize PINK1 on mitochondria, the biological significance for mitochondrial localization of SARM1 is still unclear. The relationship between mitochondrial quality control mechanisms and programmed axon death also needs to be clarified. Chronic acrylamide (ACR) intoxication cause typical pathology of axon degeneration involving early axon loss. Here, we demonstrated that the SARM1 dependent Wallerian axon self-destruction pathway was activated following ACR intoxication. Moreover, increased SARM1 was observed on the mitochondria, which interfered with the mitochondrial quality control mechanisms. As a protective response to stress, mitochondrial components enriched in SARM1 were isolated from the mitochondrial network through an increased fission process and were degraded in an autophagy-dependent manner. Importantly, rapamycin (RAPA) administration eliminated mitochondrial accumulated SARM1 and inhibited axon loss. Thus, mitochondrial localization of SARM1 may be complement to the coordinated activity of NMNAT2 and SARM1, and may be part of the self-limiting molecular mechanisms of programmed axon death. In the early latent period, the mitochondrial localization of SARM1 will help it to be isolated by the mitochondrial network and to be degraded through mitophagy to maintain local axon homeostasis. When the mitochondrial quality control mechanisms are broken down, SARM1 will cause irreversible damage for axon death.

scholarly journals mRNA quality control goes transcriptional

2013 ◽  
Vol 41 (6) ◽  
pp. 1666-1672 ◽  
Author(s):  
Cornelia Kilchert ◽  
Lidia Vasiljeva
Keyword(s):  
Quality Control ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Mrna Processing ◽  
Transcriptional Level ◽  
Control Mechanisms ◽  
Generate Functional ◽  
Eukaryotic Mrnas ◽  
Nuclear Exosome ◽  
Rna Polymerase Ii Transcription

Eukaryotic mRNAs are extensively processed to generate functional transcripts, which are 5′ capped, spliced and 3′ polyadenylated. Accumulation of unprocessed (aberrant) mRNAs can be deleterious for the cell, hence processing fidelity is closely monitored by QC (quality control) mechanisms that identify erroneous transcripts and initiate their selective removal. Nucleases including Xrn2/Rat1 and the nuclear exosome have been shown to play an important role in the turnover of aberrant mRNAs. Recently, with the growing appreciation that mRNA processing occurs concomitantly with polII (RNA polymerase II) transcription, it has become evident that QC acts at the transcriptional level in addition to degrading aberrant RNAs. In the present review, we discuss mechanisms that allow cells to co-transcriptionally initiate the removal of RNAs as well as down-regulate transcription of transcripts where processing repeatedly fails.

scholarly journals Quality Control Mechanisms in Bacterial Translation

Acta Naturae ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 32-44
Author(s):  
Anastasiia S. Zarechenskaia ◽  
Petr V. Sergiev ◽  
Ilya A. Osterman
Keyword(s):  
Quality Control ◽  
Cell Viability ◽  
Functional Role ◽  
Control Mechanisms ◽  
Cultivation Conditions ◽  
Ribosome Stalling ◽  
Hydrolysis Of ◽  
Bacterial Translation

Ribosome stalling during translation significantly reduces cell viability, because cells have to spend resources on the synthesis of new ribosomes. Therefore, all bacteria have developed various mechanisms of ribosome rescue. Usually, the release of ribosomes is preceded by hydrolysis of the tRNApeptide bond, but, in some cases, the ribosome can continue translation thanks to the activity of certain factors. This review describes the mechanisms of ribosome rescue thanks to trans-translation and the activity of the ArfA, ArfB, BrfA, ArfT, HflX, and RqcP/H factors, as well as continuation of translation via the action of EF-P, EF-4, and EttA. Despite the ability of some systems to duplicate each other, most of them have their unique functional role, related to the quality control of bacterial translation in certain abnormalities caused by mutations, stress cultivation conditions, or antibiotics.

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