Disruption of the histone H3 cupric reductase activity prevents global transcriptional rewiring when YFH1 is diminished
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE176575 | GEO | 2021/12/21
REPOSITORIES: GEO
Similar Datasets
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:Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN depleted cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.
2023-12-27 | PXD045443 | Pride
Project description:Iron-sulfur (Fe-S) clusters are ubiquitous metallocofactors involved in redox chemistry, radical generation, and gene regulation. Common methods to monitor Fe-S clusters include spectroscopic analysis of purified proteins, and auto-radiographic visualization of radiolabeled iron distribution in proteomes. Here, we report a chemoproteomic strategy that monitors changes in the reactivity of Fe-S cysteine ligands to inform on Fe-S cluster occupancy. We highlight the utility of this platform in E. coli by: (1) demonstrating global disruptions in Fe-S incorporation in cells cultured under iron-depleted conditions; (2) determining Fe-S client proteins reliant on three scaffold/carrier proteins within the Isc Fe-S biogenesis pathway; and, (3) identifying two previously unannotated Fe-S proteins, TrhP and DppD. In summary, the chemoproteomic strategy described herein is a powerful tool that reports on Fe-S cluster incorporation directly within a native proteome, and enables the interrogation of Fe-S biogenesis pathways, and the identification of previously uncharacterized Fe-S proteins.
2024-05-22 | PXD026488 | Pride
Project description:Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed genetic interaction mapping in control or FXN edited cells. This screen identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector.
2023-12-18 | GSE242192 | GEO
Project description:Fe-S cluster proteins are involved in fundamental processes such as electron transfer, gene regulation, and DNA repair in diverse bacteria. Since Fe-S clusters are susceptible to damage by oxidative and nitrosative stress conditions, bacteria harbour systems such as ISC (iron-sulfur cluster assembly) and SUF (sulfur mobilization) to regulate Fe-S homeostasis. Fe-S cluster production is tightly regulated so as to promote Fe-S formation when the necessity for clusters is heightened (e.g., ROI/RNI/iron limitation) and to limit unnecessary production when the demand is low (e.g., hypoxia). Deregulation of Fe-S cluster biogenesis can lead to the accumulation of metabolic poisons such as polysulfides and reactive oxygen species. The human pathogen, Mycobacterium tuberculosis (Mtb) exploits several Fe-S containing proteins to maintain cellular homeostasis and survival in an antagonistic host environment. The Mtb genome encodes an atypical Suf system (Rv1460-Rv1466;sufRBDCSUT) as the only complete Fe-S cluster biogenesis machinery. Expression of sufR and the complete operon was shown to be upregulated upon exposure to nitrosative stresses. Thus, we did transcriptomic study of sufR deleted strain upon exposure to 0.5 mM DETA-NO to study comprehensively the suf regulon in response to ROI/RNI stress and what are the underlying regulatory mechanisms.
2021-07-15 | GSE154169 | GEO
Project description:Iron-sulfur (Fe-S) clusters are required for essential biological pathways, including respiration and isoprenoid biosynthesis. Complex Fe-S cluster biogenesis systems have evolved to maintain an adequate supply of this critical protein cofactor. In Escherichia coli, two Fe-S biosynthetic systems, the “housekeeping” Isc and “stress responsive” Suf pathways, interface with a network of cluster trafficking proteins, such as ErpA, IscA, SufA, and NfuA. GrxD, a Fe-S cluster-binding monothiol glutaredoxin, also participates in Fe-S protein biogenesis in both prokaryotes and eukaryotes. Previous studies in E. coli showed that the ∆grxD mutation causes sensitivity to iron depletion, spotlighting a critical role for GrxD under conditions that disrupt Fe-S homeostasis. Here, we utilized a global chemoproteomic mass spectrometry (MS) approach to analyse the contribution of GrxD to the Fe-S proteome. Our results demonstrate that 1) GrxD is required for biogenesis of a specific subset of Fe-S proteins under iron-depleted conditions, 2) GrxD is required for cluster delivery to ErpA under iron limitation, 3) GrxD is functionally distinct from other Fe-S trafficking proteins and, 4) GrxD Fe-S cluster binding is responsive to iron limitation. All these results lead to the proposal that GrxD is required to maintain Fe-S cluster delivery to the essential trafficking protein ErpA during iron limitation conditions.
2024-07-13 | PXD053317 | Pride
Project description:The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play structural roles during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We have found that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3. Additionally, the assembly of the small subunit depends on METTL17, recently reported to contain a [4Fe-4S] cluster, which we found to be inserted via ISCA1-NFU1. Consistently, fibroblasts from patients suffering from “multiple mitochondrial dysfunction” syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, the mitoribosomal [2Fe-2S] clusters sense changes in the redox environment. In this way, the mitoribosome checks the availability and stability of mitochondrial Fe-S clusters to regulate organellar protein synthesis accordingly.
2024-01-26 | PXD039321 | Pride
Project description:Iron-sulphur (Fe-S) clusters are ensembles of iron and sulphide centres. They are found in all life forms and are important components of many enzymes involved in diverse cellular processes, including respiration, DNA synthesis or gene regulation. However, the increase in oxygen after the emergence of oxygenic photosynthesis created a threat to Fe–S proteins and, consequently, to the organisms relying on them. Therefore, bacteria have evolved mechanisms to maintain a precise intracellular iron concentration. A major role of IscR in R. sphaeroides iron dependent regulation was suggested in a bioinformatic study , which predicted a binding site in the upstream regions of several iron uptake genes. Most known IscR proteins have Fe-S clusters featuring (Cys)3(His)1 ligation. However, IscR proteins from Rhodobacteraceae harbour only one Cys residue and it was considered unlikely that they can ligate an Fe-S cluster. In this study, the role of R. sphaeroides IscR as transcriptional regulator and sensor of the Fe-S cluster status of the cell was analysed. The results provide evidence that R. sphaeroides IscR functions as transcriptional repressor of genes involved in iron metabolism by binding to the predicted DNA binding motif. Furthermore, IscR possesses a unique Fe-S cluster ligation scheme with only a single cysteine involved.
2015-02-03 | GSE65537 | GEO
Project description:Iron - sul fur (Fe -S) clusters are essential cofactors that enable proteins to transport electrons , sense signals or catalyze chemical reactions . The maturation of dozens of Fe - S proteins in various compartments of every eukaryotic cell is driven by several assembly pathways. The ubiquitous cytosolic Fe - S cluster assembly (CIA) pathway, typically composed of eight highly conserved proteins, depends on mitochondrial Fe -S cluster assembly (ISC) machinery . Giardia intestinalis contains one of the smallest eukaryotic genomes and the mitosome, an extremely reduced mitochondrion . Because the only pathway known to be retained within this organelle is the synthesis of Fe -S clusters mediated by ISC machinery, a likely function of the mitosome is to cooperate with the CIA pathway. We investigated the cellular localization of CIA components in G. intestinalis and the origin and distribution of CIA -related components and Tah18 -like proteins in other Metamonada. We show that ortholog s of Tah18 and Dre2 are missing in these eukaryotes. In Giardia, all CIA components are exclusively cytosolic , with the important exception of Cia2 and two Nbp35 paralogs, which are also present in the mitosomes. We propose that the dual localization of Cia2 and Nbp35 proteins in Giardia might represent a novel connection between the ISC and the CIA Pathways.
2016-09-29 | PXD004722 | Pride
Project description:This model is described in the article:
Kinetics of histone gene expression during early development of Xenopus laevis.
Koster JG, Destrée OH and Westerhoff HV. J Theor Biol.
1988 Nov 21;135(2):139-67. PMID: 3267765
Abstract:
Using literature data for transcriptional and translational rate constants, gene copy numbers, DNA concentrations, and stability constants, we have calculated the expected concentrations of histones and histone mRNA during embryogenesis of Xenopus laevis. The results led us to conclude that: (i) for X. laevis the gene copy number of the histone genes is too low to ensure the synthesis of sufficient histones during very early development, inheritance from the oocyte of either histone protein or histone mRNA (but not necessarily both) is necessary; (ii) from the known storage of histones in the oocyte and the rates of histone synthesis determined by Adamson and Woodland (1977), there would be sufficient histones to structure the newly synthesized DNA up to gastrulation but not thereafter (these empirical rates of histone synthesis may be underestimates); (iii) on the other hand, the amount of H3 mRNA recently observed during early embryogenesis (Koster, 1987, Koster et al., 1988) could direct a higher and sufficient synthesis of H3 protein, also after gastrulation. We present a quantitative model that accounts both for the observed H3 mRNA concentration as a function of time during embryogenesis and for the synthesis of sufficient histones to structure the DNA throughout early embryogenesis. The model suggests that X. laevis exhibits a major (i.e. some 14-fold) reduction in transcription of histone genes approximately 11 hours after fertilization. This reduction could be due to a decrease in the number of transcribed histone genes, a decreased rate constant of transcription with continued transcription of all the histone genes, and/or a reduction in the time during the cell cycle in which histone mRNA synthesis takes place. Alternatively, the histone mRNA stability might decrease approximately 16-fold 11 hours after fertilization.
This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL5954483266 | BioModels