Abstract
Bisphenol A (BPA) forms the backbone of plastics and epoxy resins used to produce packaging for various foods and beverages. BPA is also an estrogenic disruptor, interacting with human estrogen receptors (ER) and other related nuclear receptors. Nevertheless, the effects of BPA on human health remain unclear. The present study identified DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a novel BPA-binding protein. DNA-PKcs, in association with the Ku heterodimer (Ku70/80), is a critical enzyme involved in the repair of DNA double-strand breaks. Low levels of DNA-PK activity are previously reported to be associated with an increased risk of certain types of cancer. Although the Kd for the interaction between BPA and a drug-binding mutant of DNA-PKcs was comparatively low (137 nM), high doses of BPA were required before cellular effects were observed (100–300 μM). The results of an in vitro kinase assay showed that BPA inhibited DNA-PK kinase activity in a concentration-dependent manner. In M059K cells, BPA inhibited the phosphorylation of DNA-PKcs at Ser2056 and H2AX at Ser139 in response to ionizing radiation (IR)-irradiation. BPA also disrupted DNA-PKcs binding to Ku70/80 and increased the radiosensitivity of M059K cells, but not M059J cells (which are DNA-PKcs-deficient). Taken together, these results provide new evidence of the effects of BPA on DNA repair in mammalian cells, which are mediated via inhibition of DNA-PK activity. This study may warrant the consideration of the possible carcinogenic effects of high doses of BPA, which are mediated through its action on DNA-PK.
Highlights
Bisphenol A (BPA), 2,2-bis(4-hydroxyphenyl) propane (Fig. 1A), is widely used as a monomer in plastic products, including polycarbonate and other epoxy resins, which are used to coat food and drink cans, nursing bottles, dental sealants and many other items [1]
Binding of BPA to DNA-PKcs To identify binding to BPA (Fig. 1A), affinity purification was performed using ferrite-glycidyl methacrylate (FG) beads (Fig. 1B)
DDNA-PKcs#3 and DDNA-PKcs#6 showed strong binding to BPA (Fig. 2B lanes 7–9 and 16–18). These results suggest that the #3 and/or #6 regions are important for binding between BPA and DNA-PKcs
Summary
Bisphenol A (BPA), 2,2-bis(4-hydroxyphenyl) propane (Fig. 1A), is widely used as a monomer in plastic products, including polycarbonate and other epoxy resins, which are used to coat food and drink cans, nursing bottles, dental sealants and many other items [1]. Annual worldwide production of BPA is approximately 3 million tons. When these plastics are treated with harsh detergents or acidic or high-temperature liquids, BPA can be released, resulting in daily (albeit unintentional) ingestion of BPA in foods and drinks, via inhalation, and/or by absorption through the skin [2]. BPA shows reproductive and chronic toxicity [4]. The no observable adverse effect level for BPA was, reported in vivo even at intake of
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