hMSH2 Recruits ATR to DNA Damage Sites for Activation during DNA Damage-induced Apoptosis
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DNA damage response (DDR) activates a complex signaling network that triggers DNA repair, cell cycle arrest, and/or cell death. Depending on the type and severity of DNA lesion, DDR is controlled by "master" regulators including ATM and ATR protein kinases. Cisplatin, a major chemotherapy drug that cross-links DNA, induces ATR-dependent DDR, resulting in apoptosis. However, it is unclear how ATR is activated. To identify the key regulators of ATR, we analyzed the proteins that associate with ATR after cisplatin treatment by blue native-PAGE and co-immunoprecipitation. The mismatch repair protein hMSH2 was found to be a major ATR-binding protein. Functionally, ATR activation and its recruitment to nuclear foci during cisplatin treatment were attenuated, and DNA damage signaling, involving Chk2, p53, and PUMA-α, was suppressed in hMSH2-deficient cells. ATR activation induced by the DNA methylating agent N-methyl-N-nitrosourea was also shown to be hMSH2-dependent. Intriguingly, hMSH2-mediated ATR recruitment and activation appeared independent of replication protein A, Rad17, and the Rad9-Hus1-Rad1 protein complex. Together the results support a hMSH2-dependent pathway of ATR activation and downstream Chk2/p53 signaling.
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MSH2 recruits ATR to damage sites caused by N-methyl-N-nitrosourea independently of the 9-1-1 complex, Rad17, and RPA.
“MSH2 recruits ATR to damage sites induced by another DNA methylating agent N-methyl-N-nitrosourea, which is independent of the 9-1-1 complex, Rad17, and RPA [217]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [217]
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- Authors
- Pabla, N., Ma, Z., McIlhatton, M. A., Fishel, R., & Dong, Z.
- Affiliations
- Augusta University (US)
- The Ohio State University Wexner Medical Center (US)
- Corresponding author
- Dong, Zheng
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 286
- Issue
- 12
- Pages
- 10411-10418
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3060494
- OpenAlex
- W2084740093
- Cited by
- 107
- References
- 47
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 7 · 2022: 6 · 2021: 14 · 2020: 1 · 2019: 9 · 2018: 3 · 2017: 6 · 2016: 8 · 2015: 9 · 2014: 9 · 2013: 11 · 2012: 10
- FWCI
- 4.55
- 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
- U.S. Department of Veterans Affairs
- National Institutes of Health (GM080176)
- National Cancer Institute (CA067007, R01CA067007)
- National Institute of General Medical Sciences (GM080176, R01GM080176)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK087843, DK058831, R01DK087843, R01DK058831)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- MSH2, DNA damage response, cisplatin, DNA damage-induced apoptosis, p53, N-methyl-N-nitrosourea, DNA mismatch repair, replication protein A, protein-protein interaction
- MeSH terms
- Alkylating Agents, Animals, Cell Nucleus, Cisplatin, Cross-Linking Reagents, DNA Damage, HeLa Cells, Humans, Methylnitrosourea, Mice, Mutant Strains, Signal Transduction, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Active Transport, Cell Nucleus, Mice, Replication Protein A, MutS Homolog 2 Protein, HEK293 Cells, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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