4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest by Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/Checkpoint Kinase 1 (Chk1) Signaling Pathway
Open accessAbstract
4-Hydroxynonenal (HNE) has been widely implicated in the mechanisms of oxidant-induced toxicity, but the detrimental effects of HNE associated with DNA damage or cell cycle arrest have not been thoroughly studied. Here we demonstrate for the first time that HNE caused G 2 /M cell cycle arrest of hepatocellular carcinoma HepG2 (p53 wild type) and Hep3B (p53 null) cells that was accompanied with decreased expression of CDK1 and cyclin B1 and activation of p21 in a p53-independent manner. HNE treatment suppressed the Cdc25C level, which led to inactivation of CDK1. HNE-induced phosphorylation of Cdc25C at Ser-216 resulted in its translocation from nucleus to cytoplasm, thereby facilitating its degradation via the ubiquitin-mediated proteasomal pathway. This phosphorylation of Cdc25C was regulated by activation of the ataxia telangiectasia and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) pathway. The role of HNE in the DNA double strand break was strongly suggested by a remarkable increase in comet tail formation and H2A.X phosphorylation in HNE-treated cells in vitro . This was supported by increased in vivo phosphorylation of H2A.X in mGsta4 null mice that have impaired HNE metabolism and increased HNE levels in tissues. HNE-mediated ATR/Chk1 signaling was inhibited by ATR kinase inhibitor (caffeine). Additionally, most of the signaling effects of HNE on cell cycle arrest were attenuated in hGSTA4 transfected cells, thereby indicating the involvement of HNE in these events. A novel role of GSTA4-4 in the maintenance of genomic integrity is also suggested. Background: HNE is an important signaling molecule. Results: HNE induces G 2 /M cell cycle arrest and phosphorylation of H2A.X. ATR/Chk1-mediated regulation of Cdc25C and activation of p21 is the predominant mechanism of HNE-induced cell cycle arrest. GSTA4-4 overexpression inhibits HNE-induced cell arrest. Conclusion: HNE causes DNA damage and G 2 /M arrest. Significance: HNE and GSTA4-4 play a role in the maintenance of genomic integrity.
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4-Hydroxynonenal induces caffeine-sensitive ATR phosphorylation at serine 428 and Chk1 phosphorylation at serine 296.
“HNE also induces caffeine-sensitive ATR phosphorylation at Serine 428 and Chk1 phosphorylation at Serine 296 [147].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [147]
4-Hydroxynonenal-induced double-strand breaks enhance comet tail formation and H2AX phosphorylation in hepatocellular carcinoma cells, suggesting ATM activation.
“4-Hydroxynonenal (HNE)-induced DSBs enhance comet tail formation and H2AX phosphorylation in hepatocellular carcinoma cells, suggesting ATM activation [147–149].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [147]
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References 76 · Cited by 55
- Authors
- Chaudhary, P., Sharma, R., Sahu, M., Vishwanatha, J. K., Awasthi, S., & Awasthi, Y. C.
- Affiliations
- University of North Texas Health Science Center (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 288
- Issue
- 28
- Pages
- 20532-20546
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3711318
- OpenAlex
- W1985803032
- Cited by
- 55
- References
- 76
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 8 · 2015: 5 · 2014: 10
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Eye Institute (R01EY004396, EY004396)
- National Cancer Institute (CA 77495, R01CA077495)
- National Institute of Environmental Health Sciences (ES012171, R01ES012171)
- National Institute on Minority Health and Health Disparities (P20MD006882)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- 4-hydroxynonenal, G2/M cell cycle arrest, ATR-Chk1 signaling, Cdc25C phosphorylation, CDK1, cyclin B1, p21, H2AX phosphorylation, DNA double-strand breaks, hepatocellular carcinoma, oxidative DNA damage, genome stability, caffeine
- MeSH terms
- Checkpoint Kinase 1, Aldehydes, Animals, Cell Survival, Glutathione Transferase, Histones, Humans, Liver, Phosphorylation, Protein Kinases, Blotting, Western, Signal Transduction, Cysteine Proteinase Inhibitors, Tumor Suppressor Protein p53, CDC2 Protein Kinase, Protein Serine-Threonine Kinases, Mice, Knockout, Microscopy, Confocal, Cell Cycle Proteins, RNA Interference, Cell Line, Tumor, Mice, Cyclin B1, Hep G2 Cells, G2 Phase Cell Cycle Checkpoints, Ataxia Telangiectasia Mutated Proteins
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