MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation
Open accessAbstract
The mismatch repair proteins function upstream in the DNA damage signaling pathways induced by the DNA methylating agent N -methyl- N ′ - nitro- N -nitrosoguanidine (MNNG). We report that MSH2 (MutS homolog 2) protein interacts with the ATR (ATM- and Rad3-related) kinase to form a signaling module and regulate the phosphorylation of Chk1 and SMC1 (structure maintenance of chromosome 1). We found that phosphorylation of Chk1 by ATR also requires checkpoint proteins Rad17 and replication protein A. In contrast, phosphorylation of SMC1 by ATR is independent of Rad17 and replication protein A, suggesting that the signaling pathway leading to SMC1 phosphorylation is distinct from that mediated by the checkpoint proteins. In addition, both MSH2 and Rad17 are required for the activation of the S-phase checkpoint to suppress DNA synthesis in response to MNNG, and phosphorylation of SMC1 is required for cellular survival. These data support a model in which MSH2 and ATR function upstream to regulate two branches of the response pathway to DNA damage caused by MNNG.
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In mismatch repair, ATR is recruited by MSH2 and the RPA-ATRIP complex; MSH2 interacts with ATR to form a signaling module and regulates phosphorylation of Chk1 and SMC1.
“Similarly, in the mismatch repair pathway, ATR is recruited by the early damage recognition factor, MSH2, and the RPA-ATRIP complex. MSH2 interacts with ATR to form a signaling module and regulates the phosphorylation of Chk1 and SMC1 [40].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [40]
In mismatch repair, lesion recognition factors and RPA-coated ssDNA recruit ATR to the damage site.
“However, in case of mismatch repair, ATR is recruited to the damage site by the lesion recognition factors and also by the RPA-coated ssDNA [40].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [40]
After MNNG-induced DNA damage, MSH2 associates with ATR/ATRIP and controls MNNG-induced phosphorylation of Chk1 at serine 317 and SMC1 at serine 966.
“MSH2 associates with ATR/ATRIP and regulates MNNG-induced phosphorylation of Chk1 at Serine 317 and SMC1 at Serine 966 [212]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [212]
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“MSH2 interacts with ATR to form a signaling module and regulates the phosphorylation of Chk1 and SMC1 [40].”
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- Authors
- Wang, Y., & Qin, J.
- Affiliations
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
- Baylor College of Medicine (US)
- Corresponding author
- Qin, Jun
- ORCID
- Qin, Jun
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-12-03
- Volume
- 100
- Issue
- 26
- Pages
- 15387-15392
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC307577
- OpenAlex
- W2115512932
- Cited by
- 181
- References
- 27
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 10 · 2015: 8 · 2014: 7 · 2013: 11 · 2012: 5
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- National Institutes of Health
- National Cancer Institute (R01CA084199, CA84199)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- MSH2, ATR kinase, DNA mismatch repair, DNA damage response, DNA methylation, MNNG, Chk1 phosphorylation, Rad17, replication protein A, S-phase checkpoint
- MeSH terms
- Cell Line, Cell Survival, DNA Damage, DNA Repair, DNA-Binding Proteins, HeLa Cells, Humans, Kinetics, Methylnitronitrosoguanidine, Phosphorylation, Proto-Oncogene Proteins, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, DNA Methylation, Base Pair Mismatch, MutS Homolog 2 Protein, Ataxia Telangiectasia Mutated Proteins
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