ArticleNucleic acids research2016
The C/ebp-Atf response element (CARE) location reveals two distinct Atf4-dependent, elongation-mediated mechanisms for transcriptional induction of aminoacyl-tRNA synthetase genes in response to amino acid limitation.
Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 40 citations in OpenAlex.
- ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.Nature communications · 2026Article
- PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.Nature cardiovascular research · 2026Article
- Epigenetic drugs in cancer therapy: mechanisms, immune modulation, and therapeutic applications.Molecular biomedicine · 2025Review
- Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.Nature aging · 2025Article
- White Adipocyte Stem Cell Expansion Through Infant Formula Feeding: New Insights into Epigenetic Programming Explaining the Early Protein Hypothesis of Obesity.International journal of molecular sciences · 2025Review
- [Integrative transcriptomics-metabolomics approach to identify metabolic pathways regulated by glutamine synthetase activity].Se pu = Chinese journal of chromatography · 2025Article
- Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells.Nature communications · 2025Article
- Targeting NAT10 inhibits osteosarcoma progression via ATF4/ASNS-mediated asparagine biosynthesis.Cell reports. Medicine · 2024Article
- Lineage-determining transcription factor-driven promoters regulate cell type-specific macrophage gene expression.Nucleic acids research · 2024Article
- Article
- Genome-wide census of ATF4 binding sites and functional profiling of trait-associated genetic variants overlapping ATF4 binding motifs.PLoS genetics · 2023Article
- The transcription regulator ATF4 is a mediator of skeletal muscle aging.GeroScience · 2023Article
- Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".Cell reports · 2023Article
- Determination of in vitro hepatotoxic potencies of a series of perfluoroalkyl substances (PFASs) based on gene expression changes in HepaRG liver cells.Archives of toxicology · 2023Article
- RASSF1 is identified by transcriptome coordination analysis as a target of ATF4.FEBS open bio · 2023Article
- A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response.Frontiers in molecular neuroscience · 2023Review
- ATF4-dependent fructolysis fuels growth of glioblastoma multiforme.Nature communications · 2022Article
- Disruption of mitochondrial complex III in cap mesenchyme but not in ureteric progenitors results in defective nephrogenesis associated with amino acid deficiency.Kidney international · 2022Article
- Functional and pathologic association of aminoacyl-tRNA synthetases with cancer.Experimental & molecular medicine · 2022Review
- FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction.Science advances · 2022Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The response to amino acid (AA) limitation of the entire aminoacyl-tRNA synthetase (ARS) gene family revealed that 16/20 of the genes encoding cytoplasmic-localized enzymes are transcriptionally induced by activating transcription factor 4 (Atf4) via C/ebp-Atf-Response-Element (CARE) enhancers. In contrast, only 4/19 of the genes encoding mitochondrial-localized ARSs were weakly induced. Most of the activated genes have a functional CARE near the transcription start site (TSS), but for others the CARE is downstream. Regardless of the location of CARE enhancer, for all ARS genes there was constitutive association of RNA polymerase II (Pol II) and the general transcription machinery near the TSS. However, for those genes with a downstream CARE, Atf4, C/ebp-homology protein (Chop), Pol II and TATA-binding protein exhibited enhanced recruitment to the CARE during AA limitation. Increased Atf4 binding regulated the association of elongation factors at both the promoter and the enhancer regions, and inhibition of cyclin-dependent kinase 9 (CDK9), that regulates these elongation factors, blocked induction of the AA-responsive ARS genes. Protein pull-down assays indicated that Atf4 directly interacts with CDK9 and its associated protein cyclin T1. The results demonstrate that AA availability modulates the ARS gene family through modulation of transcription elongation.
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