Selenium Compounds Activate ATM-dependent DNA Damage Response via the Mismatch Repair Protein hMLH1 in Colorectal Cancer Cells*

Abstract

Selenium is an essential nutrient widely distributed in organic forms in certain foods and inorganic forms in soil. Selenium exerts its anticarcinogenic effects mainly through selenoproteins at nutritional levels and through selenium metabolites, including reactive oxygen species (ROS), 3 at supranutritional levels (1, 2). Animal and epidemiological studies strongly implicate selenium as an effective chemoprevention agent against colon cancer (3-6); however, the Nutritional Prevention of Cancer Trial and the recent Selenium and Vitamin E Cancer Prevention Trial reported mixed results on the efficacy of selenium in suppressing prostate cancer (7-9). Whatever the reason, the molecular mechanism by which selenium mitigates colorectal tumorigenesis is largely unknown.The majority of colorectal cancers are characterized by microsatellite instability due to a defective MMR system (10, 11). The MMR system senses DNA base mismatch after DNA replication and provokes repair, checkpoint and apoptotic responses (12). Among the many human MMR proteins, hMLH1 (human MutL homologue-1) and hPMS2 (human post-meiotic segregation protein-2) form a complex that recognizes and stabilizes mismatched DNA at an early stage and facilitates the DNA damage response (13). Somatic mutations in MMR genes and epigenetic silencing of hMLH1 expression are observed in a significant portion of sporadic colorectal cancers (8, 14), whereas germ line mutations in hMLH1 account for 60% of the autosomal dominant nonpolyposis colon cancer. Loss of both hMLH1 and hMSH2 (human MutS homologue-2) is associated with complete inactivation of MMR, whereas defects in other MMR proteins result in only partial MMR deficiency (15).The G 2 /M checkpoint prevents damaged cells from entering mitosis by coordinating DNA repair and/or apoptosis pathways. In response to DNA damage, hMLH1 can regulate G 2 /M transition through Cdc2 protein (16), and ATM kinase is implicated in G 2 /M checkpoint response (17-19). Moreover, a linkage between hMLH1 and ATM after DNA damage has been demonstrated (20,21). We have shown recently that selenium compounds at doses Յ LD 50 can activate DNA damage response through ATM and ROS in noncancerous but not in cancerous cells (22). In the current study, we hypothesized that lack of a G 2 /M checkpoint response renders the hMLH1-deficient HCT 116 cells resistant to selenium-induced DNA damage response. By employing isogenic cell lines with or without hMLH1 expression, we show herein that hMLH1 is required for

Selenoprotein W depletion induces a p53‐ and p21‐dependent delay in cell cycle progression in RWPE‐1 prostate epithelial cells

“…On the other hand, selenomethionine at 10-20 mM increases p53, enhances DNA repair, and improves survival of UVtreated cells via a ref1/p53/Brca1 protein complex without causing DNA damage [Seo et al, 2002;Fischer et al, 2006]. A recent study found that several small molecular weight Se compounds activate the ATM-dependent DNA damage response via reactive oxygen species [Qi et al, 2010]. In stark contrast, we observed p53-dependent cell cycle arrest from silencing of a selenoprotein, not from addition of a Se compound, and without evidence of a DNA damage response.…”

The Function and Significance of SELENBP1 Downregulation in Human Bronchial Epithelial Carcinogenic Process

“…It has been reported that selenium activated the DNA repair branch of the p53 pathway, induced nucleotide excision DNA repair, and protected normal human or mouse fibroblasts from UV-radiation [18], [19]. Recent advances showed that selenium can activate early barriers of tumorigenesis, namely senescence and DNA damage response, by rapidly activating ATM, which in turn initiates a cascade of DNA damage response and cellular senescence in non-cancerous and cancer cells [20], [21]. These studies further support that selenium can antagonize B[a]P-induced tumorigenesis.…”

“…It has been reported that selenium can inhibit carcinogen-induced covalent DNA adduct formation [14]–[17], promote DNA repair [18]–[20], and activate early barriers of tumorigenesis [21], indicating selenium can antagonize B[a]P-induced tumorigenesis. Because the anticarcinogenic effects of selenium are mediated possibly by SELENBP1, SELENBP1 downregulation is involved in LSCC carcinogenesis via increasing the susceptibility of human bronchial epithelial cells to B[a]P-induced tumorigenesis.…”

Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress

“…The selenium compound and its metabolites (e.g., Na 2 SeO 3 , MSeA, or MSeC) induce ROS, such as 8-oxo-G, and cause MLH1-mediated and G 2 /M arrest in HCT116 [172]. Notably, ATM is required for the selenium-induced MLH1-PMS2 association, which is essential for the repair efficiency [172] (Fig. 5).…”