Selenium Compounds Activate ATM-dependent DNA Damage Response via the Mismatch Repair Protein hMLH1 in Colorectal Cancer Cells*
Open accessAbstract
Epidemiological and animal studies indicate that selenium supplementation suppresses risk of colorectal and other cancers. The majority of colorectal cancers are characterized by a defective DNA mismatch repair (MMR). Here, we have employed the MMR-deficient HCT 116 colorectal cancer cells and the MMR-proficient HCT 116 cells with hMLH1 complementation to investigate the role of hMLH1 in selenium-induced DNA damage response, a tumorigenesis barrier. The ATM (ataxia telangiectasia mutated) protein responds to clastogens and initiates DNA damage response. We show that hMLH1 complementation sensitizes HCT 116 cells to methylseleninic acid, methylselenocysteine, and sodium selenite via reactive oxygen species and facilitates the selenium-induced oxidative 8-oxoguanine damage, DNA breaks, G(2)/M checkpoint response, and ATM pathway activation. Pretreatment of the hMLH1-complemented HCT 116 cells with the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl or the ATM kinase inhibitor KU55933 suppresses hMLH1-dependent DNA damage response to selenium exposure. Selenium treatment stimulates the association between hMLH1 and hPMS2 proteins, a heterodimer critical for functional MMR, in a manner dependent on ATM and reactive oxygen species. Taken together, the results suggest a new role of selenium in mitigating tumorigenesis by targeting the MMR pathway, whereby the lack of hMLH1 renders the HCT 116 colorectal cancer cells resistant to selenium-induced DNA damage response.
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Selenium compounds and their metabolites such as Na2SeO3, MSeA, or MSeC induce ROS including 8-oxo-G and cause MLH1-mediated G2/M arrest in HCT116 cells.
“The selenium compound and its metabolites (e.g., Na2SeO3, MSeA, or MSeC) induce ROS, such as 8-oxo-G, and cause MLH1-mediated and G2/M arrest in HCT116 [172].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [172]
ATM is required for selenium-induced MLH1-PMS2 association, which is essential for repair efficiency.
“Notably, ATM is required for the selenium-induced MLH1-PMS2 association, which is essential for the repair efficiency [172] (Fig. 5).”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [172]
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Yan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · see citing works
- Authors
- Qi, Y., Schoene, N. W., Lartey, F. M., & Cheng, W.-H.
- Affiliations
- University of Maryland, College Park (US)
- United States Department of Agriculture (US)
- Corresponding author
- Cheng, Wen-Hsing
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 285
- Issue
- 43
- Pages
- 33010-33017
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2963351
- OpenAlex
- W2059608502
- Cited by
- 57
- References
- 58
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 3 · 2012: 5
- FWCI
- 2.21
- 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)
- Lanzhou University Institutional Repository (submittedVersion, cc-by-nc)
- Funders
- China Scholarship Council
- Agricultural Research Service
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Organoselenium and organotellurium chemistry
- Keywords
- selenium, MLH1, DNA mismatch repair, ATM, DNA damage response, colorectal cancer, methylseleninic acid, methylselenocysteine, sodium selenite, reactive oxygen species, 8-oxoguanine, G2/M checkpoint, hPMS2, KU55933, N-acetylcysteine, HCT116 cells, carcinogenesis
- MeSH terms
- MutL Protein Homolog 1, Mismatch Repair Endonuclease PMS2, Acetylcysteine, Adenosine Triphosphatases, Antioxidants, Cysteine, DNA-Binding Proteins, Guanosine, Humans, Morpholines, Nuclear Proteins, Piperidines, Pyrones, Colorectal Neoplasms, Organoselenium Compounds, Anticarcinogenic Agents, Selenocysteine, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Sodium Selenite, Cell Cycle Proteins, Drug Resistance, Neoplasm, Tumor Suppressor Proteins, DNA Repair Enzymes, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, DNA Mismatch Repair, DNA Breaks, Ataxia Telangiectasia Mutated Proteins
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