ArticleCell cycle (Georgetown, Tex.)2012
S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde.
Article in Cell cycle (Georgetown, Tex.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 50 citations in OpenAlex.
- Damage to newly synthesized proteins is a major cause of Cd(II) toxicity counteracted by proteasomes and integrated stress response in human cells.Chemico-biological interactions · 2026Article
- Monoubiquitinated H2B, a Main Chromatin Target of Formaldehyde, Is Important for S-Phase Checkpoint Signaling and Genome Stability.Molecular carcinogenesis · 2024Article
- Ubiquitin signaling and the proteasome drive human DNA-protein crosslink repair.Nucleic acids research · 2023Article
- ATR activation by Cr-DNA damage is a major survival response establishing late S and G2 checkpoints after Cr(VI) exposure.Toxicology and applied pharmacology · 2023Article
- Oncoprotein SET dynamically regulates cellular stress response through nucleocytoplasmic transport in breast cancer.Cell biology and toxicology · 2023Article
- Vulnerability of HIF1α and HIF2α to damage by proteotoxic stressors.Toxicology and applied pharmacology · 2022Article
- Wasp venom peptide improves the proapoptotic activity of alendronate sodium in A549 lung cancer cells.PloS one · 2022Article
- Phyto-Phospholipid Conjugated Scorpion Venom Nanovesicles as Promising Carrier That Improves Efficacy of Thymoquinone against Adenocarcinoma Human Alveolar Basal Epithelial Cells.Pharmaceutics · 2021Article
- NADCell cycle (Georgetown, Tex.) · 2021Article
- Applying genome-wide CRISPR to identify known and novel genes and pathways that modulate formaldehyde toxicity.Chemosphere · 2021Article
- L-Carnitine reduces the negative effects of formalin on sperm parameters, chromatin condensation and apoptosis in mice: An experimental study.International journal of reproductive biomedicine · 2020Article
- Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging.Molecular cell · 2020Article
- TNFAIP1 Mediates Formaldehyde-Induced Neurotoxicity by Inhibiting the Akt/CREB Pathway in N2a Cells.Neurotoxicity research · 2020Article
- Vitamin C increases DNA breaks and suppresses DNA damage-independent activation of ATM by bleomycin.Free radical biology & medicine · 2019Article
- Toxicological Antagonism among Welding Fume Metals: Inactivation of Soluble Cr(VI) by Iron.Chemical research in toxicology · 2018Article
- Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells.Toxicology and applied pharmacology · 2017Article
- 20S immunoproteasomes remove formaldehyde-damaged cytoplasmic proteins suppressing caspase-independent cell death.Scientific reports · 2017Article
- Formaldehyde Is a Potent Proteotoxic Stressor Causing Rapid Heat Shock Transcription Factor 1 Activation and Lys48-Linked Polyubiquitination of Proteins.The American journal of pathology · 2016Article
- ATM and KAT5 safeguard replicating chromatin against formaldehyde damage.Nucleic acids research · 2016Article
- Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics.Environmental health perspectives · 2016Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
We examined genotoxic signaling and cell fate decisions in response to a potent DNA-protein crosslinker formaldehyde (FA). DNA-protein crosslinks (DPC) are poorly understood lesions produced by bifunctional carcinogens and several cancer drugs. FA-treated human cells showed a rapid activation of ATR kinase that preferentially targeted the p53 transcription factor at low doses and CHK1 kinase at more severe damage, producing bell-shaped and sublinear responses, respectively. CHK1 phosphorylation was transient, and its loss was accompanied by increased p53 accumulation and Ser15 phosphorylation. Activation of p53 was insensitive to inhibition of mismatch repair and nucleotide and base excision repair, excluding the role of small DNA adducts in this response. The p53-targeted signaling was transcription-independent, absent in quiescent cells and specific to S-phase in cycling populations. Unlike other S-phase stressors, FA-activated p53 was functional transcriptionally, promoted apoptosis in lung epithelial cells and caused senescence in normal lung fibroblasts. FA did not induce ATR, RAD1 or RPA foci, and p53 phosphorylation was TopBP1-independent, indicating a noncanonical mode of ATR activation. Replication arrest by FA caused a dissociation of ATR from a chromatin-loaded MCM helicase but no PCNA monoubiquitination associated with stalled polymerases. These results suggest that unlike typical DNA adducts that stall DNA polymerases, replication inhibition by bulkier DPC largely results from blocking upstream MCM helicase, which prevents accumulation of ssDNA. Overall, our findings indicate that S-phase-specific, TopBP1-independent activation of the ATR-p53 axis is a critical stress response to FA-DPC, which has implications for understanding of FA carcinogenesis.
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