Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Disruption of deoxynucleotide biosynthesis leads to RASproto-oncogene activation and perturbation of mitochondrial metabolism [DNA-seq]

ABSTRACT: Perturbation of the deoxyribonucleotide triphosphate (dNTP) pool is recognized for contributing to the mutagenic processes involved in oncogenesis. The RAS gene family encodes well characterized oncoproteins whose structure and function are among the most frequently altered in several cancers. In this work, we show that fluctuation of the dNTP pool induces CG->TA mutations across the whole genome, including RAS gene at codons for glycine 12 and 13, known hotspots in cancers. Cell culture addition of the ribonucleotide reductase inhibitor thymidine increases the mutation frequency in nuclear DNA and leads to disruption of mitochondrial metabolism. Interestingly, this effect is counteracted by the addition of deoxycytidine. Finally, screening for the loss of hydrogen bonds detecting CG->TA transition in RAS gene of 135 patients with colorectal cancer confirmed the clinical relevance of this process. All together, these data demonstrate that fluctuation of intracellular dNTP pool alters the nuclear DNA and mitochondrial metabolism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261896 | GEO | 2024/10/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Disruption of deoxynucleotide biosynthesis leads to RASproto-oncogene activation and perturbation of mitochondrial metabolism [RNA-seq]

Project description:Perturbation of the deoxyribonucleotide triphosphate (dNTP) pool is recognized for contributing to the mutagenic processes involved in oncogenesis. The RAS gene family encodes well characterized oncoproteins whose structure and function are among the most frequently altered in several cancers. In this work, we show that fluctuation of the dNTP pool induces CG->TA mutations across the whole genome, including RAS gene at codons for glycine 12 and 13, known hotspots in cancers. Cell culture addition of the ribonucleotide reductase inhibitor thymidine increases the mutation frequency in nuclear DNA and leads to disruption of mitochondrial metabolism. Interestingly, this effect is counteracted by the addition of deoxycytidine. Finally, screening for the loss of hydrogen bonds detecting CG->TA transition in RAS gene of 135 patients with colorectal cancer confirmed the clinical relevance of this process. All together, these data demonstrate that fluctuation of intracellular dNTP pool alters the nuclear DNA and mitochondrial metabolism.

2024-10-02 | GSE261895 | GEO

Transcriptional analysis of genes regulating the mitochondrial dNTP pool in muscle cells.

2013-03-08 | GSE41877 | GEO

Nucleotide pools dictate the identity and frequency of ribonucleotide incorporation in mitochondrial DNA

Project description:Previous work has demonstrated the presence of ribonucleotides in human mitochondrial DNA (mtDNA) and in the present study we use a genome-wide approach to precisely map the location of these. We find that ribonucleotides are distributed evenly between the heavy- and light-strand of mtDNA. The relative levels of incorporated ribonucleotides reflect that DNA polymerase γ discriminates the four ribonucleotides differentially during DNA synthesis. The observed pattern is also dependent on the mitochondrial deoxyribonucleotide (dNTP) pools and disease-causing mutations that change these pools alter both the absolute and relative levels of incorporated ribonucleotides. Our analyses strongly suggest that DNA polymerase γ-dependent incorporation is the main source of ribonucleotides in mtDNA and argues against the existence of a mitochondrial ribonucleotide excision repair pathway in human cells. Furthermore, we clearly demonstrate that when dNTP pools are limiting, ribonucleotides serve as a source of building blocks to maintain DNA replication and genome stability. Increased levels of embedded ribonucleotides in patient cells with disturbed nucleotide pools may constitute to a pathogenic mechanism that affects mtDNA stability and impair new rounds of mtDNA replication

2017-02-13 | GSE90054 | GEO

Mitochondrial antiviral-signalling protein is a client of the BAG6 QC complex

Project description:The heterotrimeric BAG6 complex coordinates the direct handover of newly synthesised tail-anchored (TA) membrane proteins from an SGTA-bound preloading complex to the endoplasmic reticulum (ER) delivery component TRC40. In contrast, defective precursors, including aberrant TA proteins, form a stable complex with this cytosolic protein quality control factor, enabling such clients to be either productively re-routed or selectively degraded. We identify the mitochondrial TA protein MAVS (mitochondrial antiviral-signalling protein) as an endogenous client of both SGTA and the BAG6 complex. Our data suggest that the BAG6 complex binds to a cytosolic pool of MAVS before its misinsertion into the ER membrane, from where it can subsequently be removed via ATP13A1-mediated dislocation. This BAG6-associated fraction of MAVS is dynamic and responds to the activation of an innate immune response, suggesting that BAG6 may modulate the pool of MAVS that is available for coordinating the cellular response to viral infection.

2022-04-26 | PXD030129 | Pride

Mus musculus

Project description:Transcriptional analysis of genes regulating the mitochondrial dNTP pool in muscle cells.

| PRJNA178465 | ENA

Transcriptional analysis of genes regulating the mitochondrial dNTP pool in muscle cells.

Project description:Mutations in genes involved in dNTP metabolism can lead to tissue-specific mitochondrial depletion syndromes (MDS), likely because the expression of key enzymes is reduced to critical levels in post mitotic cells. Our goal was to establish an in vitro skeletal muscle cell model to study the muscle specificity of MDS associated with mitochondrial dNTP pool imbalance. We performed a comprehensive analysis at the mRNA level of enzymes and transporters responsible for dNTP pool imbalance in muscle cells in vitro and in vivo. Agilent Mouse Oligo Arrays 4x44K were utilized to examine expression levels in proliferating and differentiated C2C12 cells as well as in the mouse EDL (fast glycolytic) and soleus (slow oxidative) muscles. The comparison of mRNA expression profiles supports the reliability of our in vitro cell system. Proliferating mouse C2C12 myoblasts were collected at about 50 percent confluence. Myoblasts were then induced to differentiate in vitro into myotubes that were harvested after 96 hours and further purified to reduce the contribution of mononucleated cells present in the culture. Gene expression in C2C12 myoblasts and myotubes was compared with fully differentiated muscle fibers in vivo. To this aim, the extensor digitorum longus (EDL) and soleus hind limb muscles were isolated from adult CD1 mice. These muscles were selected because they have different metabolic (glycolytic vs. oxidative) and twitching (fast vs. slow) properties. Triplicate total RNA samples were submitted to gene expression profiling.

2013-03-08 | E-GEOD-41877 | biostudies-arrayexpress

Gene expression of fibroblasts carrying SAMHD1 mutations or not

Project description:In mammalian cells, the catabolic activity of the dNTP triphosphohydrolase SAMHD1 sets the balance and the concentrations of the four dNTPs. Deficiency of SAMHD1 leads to unequally increased pools and marked dNTP imbalance. Although it is documented that imbalanced dNTP pool expansion increases mutation frequency in cancer cells, it is not known if the SAMHD1-induced dNTP imbalance favors accumulation of somatic mutations in non-transformed cells. Here we have investigated how fibroblasts isolated from Aicardi Goutières Syndrome (AGS) patients with mutated SAMHD1 react to the constitutive pool imbalance characterized by a huge dGTP pool. We focused on the effects on dNTP pools, cell-cycle progression, dynamics and fidelity of DNA replication, efficiency of UV-induced DNA repair. AGS fibroblasts entered senescence prematurely or upregulated genes involved in G1/S transition and DNA replication. The normally growing AGS cells exhibited unchanged DNA replication dynamics and, when quiescent, faster rate of excision repair of UV-induced DNA damages than wildtype fibroblasts. To investigate if the lack of SAMHD1 affects DNA replication fidelity we compared de novo mutations in AGS and WT cells by exome next generation sequencing. Somatic variant analysis indicated a mutator phenotype suggesting that SAMHD1 is a caretaker gene whose deficiency is per se mutagenic promoting genome instability in non-transformed cells.

2019-12-03 | GSE135652 | GEO

Control of the E. coli SOS regulon expression by intracellular dNTP pool changes

Project description:We studied SOS mutator effect mediated by recA730 and changes in the dNTP pool. We found that established dNTP pool changes resulting from deficiencies in the ndk or dcd genes, had a strongly suppressive effect on the recA730 mutator effect. To investigate whether the observed reduction in SOS mutator effect is due to lowered expression of the entire SOS regulon, we performed microarray analysis of gene expression profiles in each of the single ndk, dcd, and recA730 strains, as well as the double recA730 ndk and recA730 dcd strains.

2015-03-31 | GSE62898 | GEO

Project description:CG/PUF process driven marine RAS

| PRJNA1091149 | ENA

Ribonucleotides incorporated by the yeast mitochondrial DNA polymerase are not repaired

Project description:Misincorporation of ribonucleotides into DNA during genome replication has recently become recognized as a significant source of genomic instability. The frequency of ribonucleotides in the genome is determined by dNTP/rNTP ratios, the ability of the DNA polymerases to discriminate against ribonucleotides, and by the capacity of repair mechanisms to remove misincorporated ribonucleotides. To simultaneously compare how the nuclear and mitochondrial genomes incorporate and remove ribonucleotides, we challenged these processes by imbalancing cellular dNTP pools. Using a collection of yeast strains with altered dNTP pools, we discovered an inverse relationship between the concentration of individual dNTPs and the amount of the corresponding ribonucleotides incorporated in mitochondrial DNA, while in nuclear DNA the ribonucleotide pattern was only altered in the absence of ribonucleotide excision repair. Our analysis uncovers major differences in ribonucleotide repair between the two genomes and provides concrete evidence that yeast mitochondria lack mechanisms for repair of misincorporated ribonucleotides.

2017-11-07 | GSE100352 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data