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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE41877 | GEO | 2013/03/08

SECONDARY ACCESSION(S): PRJNA178465

REPOSITORIES: GEO

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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

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

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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

An essential role for dNTP homeostasis following CDKinduced [Pu-seq]

Project description:Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here we show that CDK-induced replication stress is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, Mus81- dependent DNA damage, and to genome instability. Cells respond to this replication stress by increasing dNTP supply through Set2-dependent MBFinduced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through loss of Set2-dependent H3K36 tri-methylation, results in further dNTP depletion due to reduced RNR expression, leading to replication catastrophe and cell death. This lethality can be rescued by increasing dNTP levels. Similarly, we find loss of the DNA integrity checkpoint results in synthetic lethality with Wee1 inactivation, which is also associated with replication collapse through critically low dNTP levels. Together, these findings support a ‘dNTP supply and demand’ model in which maintaining dNTP homeostasis is essential in preventing replication catastrophe in response to CDK-induced replication stress.

2018-05-26 | GSE113747 | GEO

Mus musculus

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

| PRJNA178465 | ENA

dNTP pools determine fork progression and origin usage under replication stress

Project description:Intracellular levels of deoxyribonucleoside triphosphate (dNTP) must be tightly regulated to preserve genome integrity. Indeed, alterations in dNTP pools have recently been associated with increased mutagenesis, genomic instability and tumorigenesis. However, the mechanisms by which low or imbalanced dNTP pools affect DNA replication remain poorly understood. Here, we have modulated the activity of ribonucleotide reductase (RNR), a key enzyme catalyzing a rate-limiting step of dNTP production, to monitor the effect of altered dNTP levels on replication dynamics in budding yeast. We show that dNTP pools are limiting for normal DNA synthesis as upregulation of RNR activity increases replication fork speed. In contrast, inhibition of RNR activity with hydroxyurea (HU) induces a sharp transition from a regular- to a slow-replication mode within minutes after S-phase entry. Interestingly, we found that upregulation of RNR activity delays this transition and that dNTP levels modulate both fork speed and origin usage under replication stress. Moreover, we report that chromosomal instability (CIN) mutants show increased dNTP pools and enhanced DNA synthesis in the presence of HU. Since upregulation of RNR allows forks to progress faster in the presence of DNA lesions, we propose that CIN mutants adapt to chronic replication stress by upregulating dNTP pools.

2012-01-01 | GSE33686 | 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. Comparison of transcriptomes of the bacterium Escherichia coli six strains: wt, dcd, ndk, recA730, recA730 dcd and recA730 ndk. All strains were derivatives of the MC4100 strain, carrying a sulA366 allele (?(argF-lac)169 sulA366). dcd and ndk alleles used were dcd::kan and ndk::cam, respectively. Strains were compared in pairs: wt vs dcd, wt vs ndk, wt vs recA730, recA730 vs recA730 dcd and recA730 vs recA730 ndk. Two or three biological replicates for each strain were used. Each biological replicate had two technical replicates with dye swapping.

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

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

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