A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's ataxia.
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ABSTRACT:
SUBMITTER: Campos OA
PROVIDER: S-EPMC8682991 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu1+ toxicity is a major determinant of cellular functional pool of Fe-S clusters. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich’s Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster-dependent metabolism and growth. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu1+ in diseases with Fe-S cluster dysfunction.
2021-10-21 | ST001954 | MetabolomicsWorkbench
Project description:Eukaryotic histone H3-H4 tetramers contain a putative copper (Cu2+) binding site at the H3-H3' dimerization interface with unknown function. The coincident emergence of eukaryotes with global oxygenation, which challenged cellular copper utilization, raised the possibility that histones may function in cellular copper homeostasis. We report that the recombinant Xenopus laevis H3-H4 tetramer is an oxidoreductase enzyme that binds Cu2+ and catalyzes its reduction to Cu1+ in vitro. Loss- and gain-of-function mutations of the putative active site residues correspondingly altered copper binding and the enzymatic activity, as well as intracellular Cu1+ abundance and copper-dependent mitochondrial respiration and Sod1 function in the yeast Saccharomyces cerevisiae The histone H3-H4 tetramer, therefore, has a role other than chromatin compaction or epigenetic regulation and generates biousable Cu1+ ions in eukaryotes.
| S-EPMC7842201 | biostudies-literature
Project description:We sought to examine whether nucleosomes participate in cellular copper homeostasis by directly catalyzing the reduction of copper, thereby producing the biousable cuprous ion. To test this hypothesis, we disrupted a potential copper coordination site of the nucleosome by mutating the histone H3 His113 residue to an asparagine (H113N) in the budding yeast. We observed that copper homeostasis was indeed perturbed in the H113N mutant. However, given the known roles of nucleosomes in regulating gene expression, it was reasonable to expect that the perturbation of copper homeostasis was due simply to a conincidental disrutpion of the tanscriptional regulation of genes important for copper metabolism. We performed polyA+ RNA sequencing of WT and H3H113N yeast strains in various conditions to assess whether gene expression alterations could account for the copper-related phenotypes.
2019-06-04 | GSE100034 | GEO
Project description:We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chemical approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chemistry addition of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe. Photoaffinity labeling in a nuclear extract prepared from human lymphoblasts with the trifunctional probe, followed by biotin addition through click chemistry, streptavidin enrichment, and Western blotting also identifies HDAC3 as the preferred cellular target of the inhibitor. Additional inhibitors with different HDAC specificity profiles were synthesized, and results from transcription experiments in FRDA cells point to a unique role for HDAC3 in gene silencing in Friedreich's ataxia.
| S-EPMC2909763 | biostudies-literature
Project description:Large-scale expansions of DNA repeats are implicated in numerous hereditary disorders in humans. We describe a yeast experimental system to analyze large-scale expansions of triplet GAA repeats responsible for the human disease Friedreich's ataxia. When GAA repeats were placed into an intron of the chimeric URA3 gene, their expansions caused gene inactivation, which was detected on the selective media. We found that the rates of expansions of GAA repeats increased exponentially with their lengths. These rates were only mildly dependent on the repeat's orientation within the replicon, whereas the repeat-mediated replication fork stalling was exquisitely orientation dependent. Expansion rates were significantly elevated upon inactivation of the replication fork stabilizers, Tof1 and Csm3, but decreased in the knockouts of postreplication DNA repair proteins, Rad6 and Rad5, and the DNA helicase Sgs1. We propose a model for large-scale repeat expansions based on template switching during replication fork progression through repetitive DNA.
| S-EPMC2722067 | biostudies-literature
Project description:Friedreich's ataxia (FRDA) is a progressive disease affecting multiple organs that is caused by systemic insufficiency of the mitochondrial protein frataxin. Current therapeutic strategies aim to elevate frataxin levels and/or alleviate the consequences of frataxin deficiency. Recent significant advances in the FRDA therapeutic pipeline are bringing patients closer to a cure.
| S-EPMC6826337 | biostudies-literature
Project description:IntroductionFriedreich's ataxia (FRDA) is a progressive, neurodegenerative disease that results in gait and limb ataxia, diabetes, cardiac hypertrophy, and scoliosis. At the cellular level, FRDA results in the deficiency of frataxin, a mitochondrial protein that plays a vital role in iron homeostasis and amelioration of oxidative stress. No cure currently exists for FRDA, but exciting therapeutic developments which target different parts of the pathological cascade are on the horizon.Areas coveredAreas covered include past and emerging therapies for FRDA, including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others.Expert opinionWhile drug discovery has been challenging, new and exciting prospective treatments for FRDA are currently on the horizon, including pharmaceutical agents and gene therapy. Agents that enhance mitochondrial function, such as Nrf2 activators, dPUFAs and catalytic antioxidants, as well as novel methods of frataxin augmentation and genetic modulation will hopefully provide treatment for this devastating disease.
| S-EPMC8018609 | biostudies-literature
Project description:Friedreich's ataxia (FRDA) is an inherited, progressive neurodegenerative disease that typically affects teenagers and young adults. Therapeutic strategies and disease insight have expanded rapidly over recent years, leading to hope for the FRDA population. There is currently no US FDA-approved treatment for FRDA, but advances in research of its pathogenesis have led to clinical trials of potential treatments. This article reviews emerging therapies and discusses future perspectives, including the need for more precise measures for detecting changes in neurologic symptoms as well as a disease-modifying agent.
| S-EPMC4768799 | biostudies-literature
Project description:BackgroundFriedreich's ataxia is an inherited, rare, progressive disorder of children and young adults. It is characterized by ataxia, loss of gait, scoliosis, cardiomyopathy, dysarthria and dysphagia, with reduced life expectancy. Alterations of respiratory dynamics and parameters are frequently observed. However, in the literature there are few, dated studies with small cohorts. Our study aims to make an objective analysis of the respiratory condition of both early and late stage FRDA patients, looking for correlations with the motor, skeletal, speech and genetic aspects of this condition.Materials and methodsThis retrospective observational study is based on the collection of clinical and instrumental respiratory data of 44 subjects between 13 and 51 years attending a tertiary rehabilitation centre in northern Italy. The analysis was carried out using Pearson's correlation test, ANOVA test and post hoc tests.ResultsData show the presence of a recurrent pattern of respiratory dysfunction of a restrictive type, with reduction in forced vital capacity and of flow and pressure parameters. The severity of the respiratory condition correlates with the disease severity (measured with disease-specific scales), with pneumophonic alterations and with the severity of the thoracic scoliotic curve.ConclusionsRespiratory function is impaired at various degrees in FRDA. The complex condition of inco-ordination and hyposthenia in FRDA affects daytime and night-time respiratory efficiency. We believe that the respiratory deficit and the inefficiency of cough are indeed a clinical problem deserving consideration, especially in the context of the concomitant postural difficulty and the possible presence of dysphagia. Therefore, the rehabilitation project for the subject with FRDA should also consider the respiratory function.
| S-EPMC9497209 | biostudies-literature
Project description:The identification of biomarkers for Friedreich’s ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, is an important goal for disease follow-up and assessment of treatments. Clinical scales are not sensitive enough to detect small, short-term changes that may be indicative of treatment effectiveness. We used differential expression, correlation with expansion size, network analysis, machine learning, and enrichment analysis to identify gene expression biomarkers which differentiated FRDA patients from both heterozygous expansion carriers and controls (821 individuals in total), resulting in a disease signature for FRDA. Our 27-gene expression panel includes genes which are linked to inflammation, lipid metabolism and apoptosis, and overlaps with previous studies and a with a novel mouse model for FRDA. Future studies should seek to expand the search for FRDA biomarkers to include changes in epigenetic regulation and protein expression.
2018-07-26 | GSE102008 | GEO