ArticleNucleic acids research2020
Inactivation of folylpolyglutamate synthetase Met7 results in genome instability driven by an increased dUTP/dTTP ratio.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it, 9 citations in OpenAlex.
- A Systematic Review of Folate and the Human Enteric Microbiome: Biological Mechanisms and Clinical Implications.International journal of molecular sciences · 2026Pooled it
- Adaptive Regulation of dNTP Homeostasis Confers Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma.Cancer research · 2026Article
- SLC46A1 deficiency-mediated folate restriction suppresses colorectal cancer progression through epigenetic-transcriptional reprogramming.Cell death & disease · 2026Article
- Elucidation and engineering mitochondrial respiratory-related genes for improving bioethanol production at high temperature inEngineering microbiology · 2024Article
- Neural Tube Defects and Folate Deficiency: Is DNA Repair Defective?International journal of molecular sciences · 2023Review
- The nucleotide metabolome of germinating Arabidopsis thaliana seeds reveals a central role for thymidine phosphorylation in chloroplast development.The Plant cell · 2022Article
- Isocratic HPLC analysis for the simultaneous determination of dNTPs, rNTPs and ADP in biological samples.Nucleic acids research · 2022Article
- Review
- Ligation of newly replicated DNA controls the timing of DNA mismatch repair.Current biology : CB · 2021Article
- Identification of MLH2/hPMS1 dominant mutations that prevent DNA mismatch repair function.Communications biology · 2020Article
- A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye and inhibitor-resistant high-fidelity DNA polymerase.Nucleic acids research · 2020Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The accumulation of mutations is frequently associated with alterations in gene function leading to the onset of diseases, including cancer. Aiming to find novel genes that contribute to the stability of the genome, we screened the Saccharomyces cerevisiae deletion collection for increased mutator phenotypes. Among the identified genes, we discovered MET7, which encodes folylpolyglutamate synthetase (FPGS), an enzyme that facilitates several folate-dependent reactions including the synthesis of purines, thymidylate (dTMP) and DNA methylation. Here, we found that Met7-deficient strains show elevated mutation rates, but also increased levels of endogenous DNA damage resulting in gross chromosomal rearrangements (GCRs). Quantification of deoxyribonucleotide (dNTP) pools in cell extracts from met7Δ mutant revealed reductions in dTTP and dGTP that cause a constitutively active DNA damage checkpoint. In addition, we found that the absence of Met7 leads to dUTP accumulation, at levels that allowed its detection in yeast extracts for the first time. Consequently, a high dUTP/dTTP ratio promotes uracil incorporation into DNA, followed by futile repair cycles that compromise both mitochondrial and nuclear DNA integrity. In summary, this work highlights the importance of folate polyglutamylation in the maintenance of nucleotide homeostasis and genome stability.
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