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The mismatch repair protein hMLH1 regulates selenium‐induced DNA damage response in colorectal cancer cells
Author(s) -
Qi Yongmei,
Schoene Norberta W,
Cheng WenHsing
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.916.8
Subject(s) - dna mismatch repair , dna damage , dna repair , colorectal cancer , genome instability , microsatellite instability , cancer research , carcinogenesis , selenium , rad50 , programmed cell death , cancer , chemistry , biology , dna , genetics , gene , apoptosis , dna binding protein , transcription factor , organic chemistry , allele , microsatellite
Epidemiological studies indicate that selenium supplementation in humans suppresses risk of colorectal and other cancers. The majority of colorectal cancer is characterized by a defective DNA mismatch repair (MMR) system. The hMLH1‐hPMS2 heterodimer plays a critical role at the early stage of MMR repair. Here, we employed HCH116 colorectal cancer cells with intrinsic hMLH1 deficiency and the cell complemented with hMLH1, and treated them with sodium selenite (2–10 μM), methane seleninic acid (2–10 μM) and methyl‐seleno‐L‐cysteine (50–300 μM). We showed that complementation of hMLH1 sensitizes HCT116 cells to cell death after treatment with the selenium compounds. Interestingly, cellular exposure to organic forms of selenium compounds resulted in increased hMLH1 protein expression and hMLH1‐hPMS2 association. Furthermore, hMLH1 is involved in proper S and G2/M phase checkpoint responses and DNA‐PK cs phosphorylation at Thr‐2647, an early event of DNA damage response, after cellular exposure to selenite. Our results suggest that DNA damage checkpoint response, a barrier of tumorigenesis, is deficient in HCT116 cells after selenium treatment. Consequently, a lack of functional hMLH1‐hPMS2 complex may predispose colorectal cancer cells to genomic instability. Grant Funding Source : University of Maryland