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Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair [glutamine]

ABSTRACT: The translation-dependent effect of amino acid bioavailability on the nature of proteins that cells express could have major consequences on their phenotype. We report that the intracellular concentration decrease of amino acids like aspartate and glutamate in a melanoma cell line exposed to anti-cancer MAPK inhibitors (MAPKi) triggers ribosomal peaks in mRNA regions enriched in codons corresponding to these amino acids and in the translation-dependent degradation of mRNAs encoding proteins enriched in these amino acids. Since aspartate- and glutamate-rich proteins are involved in cell proliferation and DNA repair, we propose that MAPKi surviving cells degrade aspartate and glutamate to generate energy which simultaneously decreases their needs through the downregulation of gene products involved in cell proliferation. Moreover, the expression level decrease of aspartate- and glutamate-rich proteins involved in DNA repair increases as a side effect the probability of DNA damages and consequently the emergence of mutated cells in response to MAPKi.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232551 | GEO | 2024/05/08

REPOSITORIES: GEO

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Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair [MAPK inhibitors]

Project description:The translation-dependent effect of amino acid bioavailability on the nature of proteins that cells express could have major consequences on their phenotype. We report that the intracellular concentration decrease of amino acids like aspartate and glutamate in a melanoma cell line exposed to anti-cancer MAPK inhibitors (MAPKi) triggers ribosomal peaks in mRNA regions enriched in codons corresponding to these amino acids and in the translation-dependent degradation of mRNAs encoding proteins enriched in these amino acids. Since aspartate- and glutamate-rich proteins are involved in cell proliferation and DNA repair, we propose that MAPKi surviving cells degrade aspartate and glutamate to generate energy which simultaneously decreases their needs through the downregulation of gene products involved in cell proliferation. Moreover, the expression level decrease of aspartate- and glutamate-rich proteins involved in DNA repair increases as a side effect the probability of DNA damages and consequently the emergence of mutated cells in response to MAPKi.

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Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair [RNA-seq]

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Regulation of gene expression by putative aspartate racemases, YgeA and AspR, in Salmonella Typhimurium

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Transcriptomic analysis of Campylobacter jejuni grown in medium containing serine as a main energy source

Project description:Campylobacter jejuni is one of the most important causes of food-borne diseases in industrialized countries. It is known that amino acids are important nutrient source for this pathogen, because C. jejuni lacks enzymes related to glycolysis. However, the characteristics on metabolism of C. jejuni grown in the nutrient restricted medium with a specific amino acid is not fully elucidated. This study shows that C. jejuni NCTC11168 grew well in the nutrient restricted medium containing serine, aspartate, glutamate, and proline. The single subtraction of serine significantly reduced the growth, while three other amino acids did not, suggesting the priority of serine among the four amino acids. In the transcriptomic analysis of C. jejuni NCTC11168 grown in medium with serine as a main energy source. Serine seemed to be sensed by some chemoreceptors and the C. jejuni might reached an adaptation stage with active growth. That is, the expression of flagellar assembly components was downregulated and the biosynthesis of multiple amino acids and nucleotide sugars were upregulated. These data suggest the higher requirement of serine as a nutrient of C. jejuni NCTC11168.

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Modern and Fossil Coral Skeletal Proteomes - Fossil Soluble Trypsin1

Project description:Here we report the first recovery, sequencing, and identification of fossil biomineral proteins from a Pleistocene invertebrate. Fossils of the Caribbean stony coral Orbicella annularis retain total hydrolyzable amino acids of a similar composition to extracts from modern O. annularis skeletons and ~10% of the modern skeletal proteome was sequenced by LC-MS/MS over multiple trials in the best-preserved fossil coral specimen. The data are rich in acidic amino acids such as aspartate and glutamate typical of skeletal proteins, and one of the four sequenced fossil proteins, a highly acidic protein, has been previously characterized in modern coral skeletons. A combination of degradation, or amino acid racemization inhibition of trypsin digestion, appears to limit greater recovery. Nevertheless, our workflow determines optimal samples for effective sequencing of fossil coral proteins, allowing comparison of modern and fossil invertebrate protein sequences, and will likely lead to further improvements of the methods. Sequencing of endogenous organic mand biotic responses to paleoenvironments.

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Project description:Adequate protein intake is crucial for animals. Despite the recent progress in understanding protein hunger and satiety in the fruit fly Drosophila melanogaster, how fruit flies assess prospective dietary protein sources and ensure protein consumption remains elusive. We show here that three specific amino acids, L-glutamate (L-Glu), L-alanine (L-Ala), and L-aspartate (L-Asp), but not the D-enantiomers, rapidly promote food consumption in fruit flies when present in food. The effect of dietary amino acids to promote food consumption is independent of mating experience and internal nutritional status. Calcium imaging experiments show that six brain neurons expressing diuretic hormone 44 (DH44) can be rapidly and directly activated by these three amino acids during feeding. Genetic analysis shows that DH44+ neurons are both necessary and sufficient for dietary amino acids to promote food consumption. By conducting single cell RNAseq analysis, we also identify a amino acid transporter, CG13248, which is highly expressed in DH44+ neurons and is required for dietary amino acids to promote food consumption. Therefore, these data suggest that dietary amino acids may enter DH44+ neurons via CG13248 and modulate their activity and hence food consumption. Taken together, these data identify an internal amino acid sensor in the fly brain that evaluate food sources post-ingestively and facilitates adequate protein intake. These results shed critical light on the regulation of protein homeostasis at organismal levels by the nervous system.

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