ATR-Chk2 Signaling in p53 Activation and DNA Damage Response during Cisplatin-induced Apoptosis
Open accessAbstract
Cisplatin is one of the most effective anti-cancer drugs; however, the use of cisplatin is limited by its toxicity in normal tissues, particularly injury of the kidneys. The mechanisms underlying the therapeutic effects of cisplatin in cancers and side effects in normal tissues are largely unclear. Recent work has suggested a role for p53 in cisplatin-induced renal cell apoptosis and kidney injury; however, the signaling pathway leading to p53 activation and renal apoptosis is unknown. Here we demonstrate an early DNA damage response during cisplatin treatment of renal cells and tissues. Importantly, in the DNA damage response, we demonstrate a critical role for ATR, but not ATM (ataxia telangiectasia mutated) or DNA-PK (DNA-dependent protein kinase), in cisplatin-induced p53 activation and apoptosis. We show that ATR is specifically activated during cisplatin treatment and co-localizes with H2AX, forming nuclear foci at the site of DNA damage. Blockade of ATR with a dominant-negative mutant inhibits cisplatin-induced p53 activation and renal cell apoptosis. Consistently, cisplatin-induced p53 activation and apoptosis are suppressed in ATR-deficient fibroblasts. Downstream of ATR, both Chk1 and Chk2 are phosphorylated during cisplatin treatment in an ATR-dependent manner. Interestingly, following phosphorylation, Chk1 is degraded via the proteosomal pathway, whereas Chk2 is activated. Inhibition of Chk2 by a dominant-negative mutant or gene deficiency attenuates cisplatin-induced p53 activation and apoptosis. In vivo in C57BL/6 mice, ATR and Chk2 are activated in renal tissues following cisplatin treatment. Together, the results suggest an important role for the DNA damage response mediated by ATR-Chk2 in p53 activation and renal cell apoptosis during cisplatin nephrotoxicity.
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An MMR protein participates in ATR activation after cisplatin-induced oxidative stress.
“This suggests the involvement of a MMR protein in ATR activation in response to cisplatin-induced oxidative stress [215, 216].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [216]
In rat kidney proximal tubular cells, cisplatin induces MSH2-mediated and ATR-dependent phosphorylation of p53 at serine 15 and Chk2 at threonine 68.
“cisplatin induces MSH2-mediated and ATR-dependent p53 phosphorylation at Serine 15 and Chk2 phosphorylation at Threonine 68 in rat kidney proximal tubular cells.”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [216]
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- Authors
- Pabla, N., Huang, S., Mi, Q.-S., Daniel, R., & Dong, Z.
- Affiliations
- Charlie Norwood VA Medical Center (US)
- Corresponding author
- Dong, Zheng
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-03
- Volume
- 283
- Issue
- 10
- Pages
- 6572-6583
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2043445391
- Cited by
- 309
- References
- 47
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 14 · 2023: 21 · 2022: 13 · 2021: 19 · 2020: 12 · 2019: 11 · 2018: 12 · 2017: 12 · 2016: 22 · 2015: 14 · 2014: 19 · 2013: 23 · 2012: 14
- FWCI
- 8.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Washington University in St. Louis
- Johns Hopkins University
- University of Virginia
- West Virginia University
- National Institutes of Health
- National Cancer Institute (R01CA125272)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Keywords
- cisplatin, ATR kinase, Chk2, p53 activation, DNA damage response, cisplatin-induced apoptosis, renal cell apoptosis, cisplatin nephrotoxicity, H2AX, dominant-negative mutant
- MeSH terms
- Checkpoint Kinase 1, Animals, Antineoplastic Agents, Cell Line, Transformed, Cisplatin, DNA Damage, DNA-Binding Proteins, Histones, Humans, Kidney Diseases, Kidney Tubules, Proximal, Neoplasms, Protein Kinases, Signal Transduction, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Gene Deletion, Cell Cycle Proteins, Tumor Suppressor Proteins, Proteasome Endopeptidase Complex, Rats, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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