ArticleProceedings of the National Academy of Sciences of the United States of America2008
DNA synthesis from unbalanced nucleotide pools causes limited DNA damage that triggers ATR-CHK1-dependent p53 activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 83 citations in OpenAlex.
- Loss of BOK increases vulnerability of p53 deficient non-small cell lung cancer cells to ATR inhibition through its role in uridine metabolism.Cell death and differentiation · 2026Article
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- Purine metabolic adaptation protects the endothelium from disturbed flow-induced DNA damage and atherosclerosis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Pan-cancer analysis of pyrimidine metabolism reveals signaling pathways connections with chemoresistance role.British journal of cancer · 2026Article
- Arginine Metabolism SupportsbioRxiv : the preprint server for biology · 2025Article
- A cytidine deaminase-like protein modulates pyrimidine nucleotide homeostasis in Trypanosoma brucei.Scientific reports · 2025Article
- Radiotherapy resistance driven by Asparagine endopeptidase through ATR pathway modulation in breast cancer.Journal of experimental & clinical cancer research : CR · 2025Article
- A mechanism of global gene expression regulation is disrupted by multiple disease states and drug treatments.PloS one · 2025Article
- Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment.Frontiers in immunology · 2025Review
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- The Loss of Tafazzin Transacetylase Activity Is Sufficient to Drive Testicular Infertility.Journal of developmental biology · 2024Article
- 8-OxodG: A Potential Biomarker for Chronic Oxidative Stress Induced by High-LET Radiation.DNA · 2024Article
- p53 activation enhances the sensitivity of non-small cell lung cancer to the combination of SH003 and docetaxel by inhibiting de novo pyrimidine synthesis.Cancer cell international · 2024Article
- Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus.Nature communications · 2024Article
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- Article
- A nuclear orthologue of the dNTP triphosphohydrolase SAMHD1 controls dNTP homeostasis and genomic stability inFrontiers in cellular and infection microbiology · 2023Article
- dTMP imbalance through thymidylate 5'-phosphohydrolase activity induces apoptosis in triple-negative breast cancers.Scientific reports · 2022Article
- Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity.Cancers · 2022Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
p53-dependent G(1) and G(2) cell cycle checkpoints are activated in response DNA damage that help to maintain genomic stability. p53 also helps to protect cells from damage that occurs during S phase, for example, when the cells are starved for DNA precursors or irradiated with a low dose of UV. p53 is activated in normal cells starved for pyrimidine nucleotides by treatment with N-(phosphonacetyl)-l-aspartate (PALA). The treated cells progress through a first S phase with kinetics similar to those of untreated cells. However, the DNA of the treated cells begins to become damaged rapidly, within 12 h, as revealed by a comet assay, which detects broken DNA, and by staining for phosphorylated histone H2AX, which accumulates at sites of DNA damage. Because the cells survive, the damage must be reversible, suggesting single-strand breaks or gaps as the most likely possibility. The transiently damaged DNA stimulates activation of ATR and CHK1, which in turn catalyze the phosphorylation and accumulation of p53. Although PALA-induced DNA damage occurs only in dividing cells, the p53 that is activated is only competent to transcribe genes such as p21 and macrophage inhibitory cytokine 1 (whose products regulate G(2) and G(1) or S phase checkpoints, respectively) after the cells have exited the S phase during which damage occurs. We propose that p53 is activated by stimulation of mismatch repair in response to the misincorporation of deoxynucleotides into newly synthesized DNA, long before the lack of pyrimidine nucleoside triphosphates causes the rate of DNA synthesis to slow appreciably.
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