scholarly journals Molecular Mechanism of Nuclear Tau Accumulation and its Role in Protein Synthesis

2020 ◽  
Author(s):  
Miguel Portillo ◽  
Ekaterina Eremenko ◽  
Shai Kaluski ◽  
Lior Onn ◽  
Daniel Stein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Protein Synthesis ◽  
Energy Production ◽  
Protein Translation ◽  
Nuclear Accumulation ◽  
Rrna Synthesis ◽  
Global Changes ◽  
Post Translational Modifications ◽  
Dna Damage Signaling

AbstractSeveral neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Tau-K174Q expressing cells showed changes in the nucleolus increasing their intensity and number, as well as in rRNA synthesis leading to an increase in protein translation and ATP reduction. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.

scholarly journals Ribosome profiling reveals a functional role for autophagy in mRNA translational control

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Juliet Goldsmith ◽  
Timothy Marsh ◽  
Saurabh Asthana ◽  
Andrew M. Leidal ◽  
Deepthisri Suresh ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Synthesis ◽  
Translational Control ◽  
Mammalian Cells ◽  
Dna Damage Repair ◽  
Protein Translation ◽  
Ribosome Profiling ◽  
Parp Inhibition ◽  
Genetic Ablation ◽  
Damage Repair

AbstractAutophagy promotes protein degradation, and therefore has been proposed to maintain amino acid pools to sustain protein synthesis during metabolic stress. To date, how autophagy influences the protein synthesis landscape in mammalian cells remains unclear. Here, we utilize ribosome profiling to delineate the effects of genetic ablation of the autophagy regulator, ATG12, on translational control. In mammalian cells, genetic loss of autophagy does not impact global rates of cap dependent translation, even under starvation conditions. Instead, autophagy supports the translation of a subset of mRNAs enriched for cell cycle control and DNA damage repair. In particular, we demonstrate that autophagy enables the translation of the DNA damage repair protein BRCA2, which is functionally required to attenuate DNA damage and promote cell survival in response to PARP inhibition. Overall, our findings illuminate that autophagy impacts protein translation and shapes the protein landscape.

scholarly journals Inhibition of Transcription Induces Phosphorylation of YB-1 at Ser102 and Its Accumulation in the Nucleus

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 104 ◽  
Author(s):  
Dmitry A. Kretov ◽  
Daria A. Mordovkina ◽  
Irina A. Eliseeva ◽  
Dmitry N. Lyabin ◽  
Dmitry N. Polyakov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Nuclear Localization ◽  
Kinase Activity ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Regulatory Mechanisms ◽  
Nuclear Accumulation ◽  
Nuclear Retention ◽  
Post Translational Modifications

The Y-box binding protein 1 (YB-1) is an RNA/DNA-binding protein regulating gene expression in the cytoplasm and the nucleus. Although mostly cytoplasmic, YB-1 accumulates in the nucleus under stress conditions. Its nuclear localization is associated with aggressiveness and multidrug resistance of cancer cells, which makes the understanding of the regulatory mechanisms of YB-1 subcellular distribution essential. Here, we report that inhibition of RNA polymerase II (RNAPII) activity results in the nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102. The inhibition of kinase activity reduces YB-1 phosphorylation and its accumulation in the nucleus. The presence of RNA in the nucleus is shown to be required for the nuclear retention of YB-1. Thus, the subcellular localization of YB-1 depends on its post-translational modifications (PTMs) and intracellular RNA distribution.

scholarly journals Transite: A computational motif-based analysis platform that identifies RNA-binding proteins modulating changes in gene expression

2018 ◽  
Author(s):  
Konstantin Krismer ◽  
Shohreh Varmeh ◽  
Molly A. Bird ◽  
Anna Gattinger ◽  
Yi Wen Kong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Protein Translation ◽  
State Transitions ◽  
Global Changes ◽  
Expression Data ◽  
Platinum Based Chemotherapy

AbstractRNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. In response to various stimuli, alterations in RBP function contribute to global changes in gene expression, but identifying which specific RBPs are responsible for the observed changes in gene expression patterns remains an unmet need. Here, we presentTransitea multi-pronged computational approach that systematically infers RBPs influencing gene expression changes through alterations in RNA stability and degradation. As a proof of principle, we applied Transite to public RNA expression data from human patients with non-small cell lung cancer whose tumors were sampled at diagnosis, or after recurrence following treatment with platinum-based chemotherapy. Transite implicated known RBP regulators of the DNA damage response and identified hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a generalizable framework for the identification of RBPs responsible for gene expression changes that drive cell-state transitions and adds additional value to the vast wealth of publicly-available gene expression data.

Abstract 355: Post-translational Modification of Histone Variants in Cardiac Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Mickey Miller ◽  
Aman Makaju ◽  
Li Wang ◽  
Sarah Franklin
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Differential Expression Analysis ◽  
Pressure Overload ◽  
Histone Variants ◽  
Neonatal Rat ◽  
Global Changes ◽  
Label Free ◽  
Post Translational Modification ◽  
Post Translational Modifications

While global changes in gene expression are a hallmark of cardiac hypertrophy, much less is known regarding the epigenetic factors driving these changes. Local chromatin packing and gene accessibility, which governs transcriptional status, has been correlated with specific post-translational modifications on the histone tails of nucleosomes occupying these regions. However, the specific alterations in histone post-translational modifications driving gene expression changes during cardiac hypertrophy are largely unknown. To identify myocyte specific changes in histone post-translational modifications during cardiac hypertrophy we performed label-free quantitation of nuclear proteins from isolated neonatal rat ventricular myocytes exposed to the hypertrophic agonists, phenylephrine and isoproterenol. Peptide samples were analyzed on a Thermo Orbitrap Velos Pro mass spectrometer using CID & HCD fragmentation. Differential expression analysis was performed using the Progenesis LC-MS software where modified histone peptides were normalized against total protein expression. We observed multiple known and novel post-translational modifications on each of the four core histones, many of which changed in the setting of hypertrophy. To validate these findings in an animal model we performed the same analysis of histone post-translational modifications from cardiac tissue of mice under basal conditions or after pressure-overload induced hypertrophy. This study provides the first global characterization of myocyte specific changes in histone post-translational modifications in cardiac hypertrophy and highlight basic mechanisms of genomic reprogramming operative in disease.

scholarly journals The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability

2021 ◽  
Vol 22 (6) ◽  
pp. 2976
Author(s):  
Amira Fitieh ◽  
Andrew J. Locke ◽  
Mobina Motamedi ◽  
Ismail Hassan Ismail
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Gene Silencing ◽  
Strand Break ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Post Translational Modifications ◽  
Dna Damage Signaling ◽  
Dna Double Strand Break ◽  
Group Protein

The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.

scholarly journals Dexrazoxane Averts Idarubicin-Evoked Genomic Damage by Regulating Gene Expression Profiling Associated With the DNA Damage-Signaling Pathway in BALB/c Mice

2017 ◽  
Vol 160 (1) ◽  
pp. 161-172 ◽  
Author(s):  
Sabry M. Attia ◽  
Ali Y. Alshahrani ◽  
Mohammed A. Al-Hamamah ◽  
Mohammed M. Attia ◽  
Quaiser Saquib ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Gene Expression Profiling ◽  
Signaling Pathway ◽  
Expression Profiling ◽  
Dna Damage Signaling ◽  
Genomic Damage

scholarly journals Endurance exercise decreases protein synthesis and ER-mitochondria contacts in mouse skeletal muscle

2019 ◽  
Vol 127 (5) ◽  
pp. 1297-1306 ◽  
Author(s):  
Audrey Merle ◽  
Maxence Jollet ◽  
Florian A. Britto ◽  
Bénédicte Goustard ◽  
Nadia Bendridi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Damage ◽  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Energy Demand ◽  
Protein Translation ◽  
Strong Increase ◽  
Hindlimb Muscles

Exercise is important to maintain skeletal muscle mass through stimulation of protein synthesis, which is a major ATP-consuming process for cells. However, muscle cells have to face high energy demand during contraction. The present study aimed to investigate protein synthesis regulation during aerobic exercise in mouse hindlimb muscles. Male C57Bl/6J mice ran at 12 m/min for 45 min or at 12 m/min for the first 25 min followed by a progressive increase in velocity up to 20 m/min for the last 20 min. Animals were injected intraperitoneally with 40 nmol/g of body weight of puromycin and euthanized by cervical dislocation immediately after exercise cessation. Analysis of gastrocnemius, plantaris, quadriceps, soleus, and tibialis anterior muscles revealed a decrease in protein translation assessed by puromycin incorporation, without significant differences among muscles or running intensities. The reduction of protein synthesis was associated with a marked inhibition of mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, a mechanism consistent with reduced translation initiation. A slight activation of AMP-activated protein kinase consecutive to the running session was measured but did not correlate with mTORC1 inhibition. More importantly, exercise resulted in a strong upregulation of regulated in development and DNA damage 1 (REDD1) protein and gene expressions, whereas transcriptional regulation of other recognized exercise-induced genes ( IL-6, kruppel-like factor 15, and regulator of calcineurin 1) did not change. Consistently with the recently discovered role of REDD1 on mitochondria-associated membranes, we observed a decrease in mitochondria-endoplasmic reticulum interaction following exercise. Collectively, these data raise questions concerning the role of mitochondria-associated endoplasmic reticulum membrane disruption in the regulation of muscle proteostasis during exercise and, more generally, in cell adaptation to metabolic stress. NEW & NOTEWORTHY How muscles regulate protein synthesis to cope with the energy demand during contraction is poorly documented. Moreover, it is unknown whether protein translation is differentially affected among mouse hindlimb muscles under different physiological exercise modalities. We showed here that 45 min of running decreases puromycin incorporation similarly in 5 different mouse muscles. This decrease was associated with a strong increase in regulated in development and DNA damage 1 protein expression and a significant disruption of the mitochondria and sarcoplasmic reticulum interaction.

Brevetoxin 2 alters expression of apoptotic, DNA damage, and cytokine genes in Jurkat cells

2010 ◽  
Vol 30 (3) ◽  
pp. 182-191 ◽  
Author(s):  
Rachel N Murrell ◽  
James E Gibson
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Sodium Channels ◽  
Marine Mammals ◽  
Jurkat Cells ◽  
Voltage Gated ◽  
Dna Damage Signaling ◽  
Voltage Gated Sodium Channels ◽  
Biological Responses ◽  
Genes Encoding

Brevetoxins are potent neurotoxins that exert their toxicity through activation of voltage-gated sodium channels. Exposure to brevetoxins cause severe respiratory inflammation in marine mammals and humans. Brevetoxin activation of voltage-gated sodium channels on immune cells can lead to several biological responses including cell proliferation, gene transcription, cytokine production and even apoptosis. Jurkat E6-1 T cells were treated with brevetoxin 2 for 4 hours at a dose previously shown to induce apoptosis and DNA damage. Changes in gene expression were then assessed via PCR arrays. Gene expression analysis revealed significant change in expression of 17 genes related to apoptosis, 21 genes related to DNA damage signaling, and 19 genes encoding common cytokines. The gene expression data supports the idea that brevetoxins trigger complex reactions involving both inflammation and cell death.

scholarly journals Collateral Victim or Rescue Worker?—The Role of Histone Methyltransferases in DNA Damage Repair and Their Targeting for Therapeutic Opportunities in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Lishu He ◽  
Gwen Lomberk
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Cancer Therapeutics ◽  
Great Promise ◽  
Cell Integrity ◽  
Post Translational Modifications ◽  
Dna Damage Signaling ◽  
Damage Repair ◽  
Chromatin Biology

Disrupted DNA damage signaling greatly threatens cell integrity and plays significant roles in cancer. With recent advances in understanding the human genome and gene regulation in the context of DNA damage, chromatin biology, specifically biology of histone post-translational modifications (PTMs), has emerged as a popular field of study with great promise for cancer therapeutics. Here, we discuss how key histone methylation pathways contribute to DNA damage repair and impact tumorigenesis within this context, as well as the potential for their targeting as part of therapeutic strategies in cancer.

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