Abstract
Silver nanoparticles (Ag-np) have been used in medicine and commercially due to their anti-microbial properties. Therapeutic potentials of these nanoparticles are being explored extensively despite the lack of information on their mechanism of action at molecular and cellular level. Here, we have investigated the DNA damage response and repair following Ag-np treatment in mammalian cells. Studies have shown that Ag-np exerts genotoxicity through double-strand breaks (DSBs). DNA-PKcs, the catalytic subunit of DNA dependent protein kinase, is an important caretaker of the genome which is known to be the main player mediating Non-homologous End-Joining (NHEJ) repair pathway. We hypothesize that DNA-PKcs is responsible for the repair of Ag-np induced DNA damage. In vitro studies have been carried out to investigate both cytotoxicity and genotoxicity induced by Ag-np in normal human cells, DNA-PKcs proficient, and deficient mammalian cells. Chemical inhibition of DNA-PKcs activity with NU7026, an ATP-competitive inhibitor of DNA-PKcs, has been performed to further validate the role of DNA-PKcs in this model. Our results suggest that Ag-np induced more prominent dose-dependent decrease in cell viability in DNA-PKcs deficient or inhibited cells. The deficiency or inhibition of DNA-PKcs renders the cells with higher susceptibility to DNA damage and genome instability which in turn contributed to greater cell cycle arrest/cell death. These findings support the fact that DNA-PKcs is involved in the repair of Ag-np induced genotoxicity and NHEJ repair pathway and DNA-PKcs particularly is activated to safeguard the genome upon Ag-np exposure.
Highlights
Nanotechnology is a rapidly growing industry which promises tremendous scientific and economic potential
We examined whether Non-homologous End-Joining (NHEJ) pathway is responsible for the repair of the DNA damage induced by Ag-np with regards to the status of DNA-PKcs in mammalian cells
Our results reveal that total DNA damage is greater in Ag-np-treated DNA-PKcs deficient or inhibited cells than DNAPKcs proficient cells or normal mammalian cells
Summary
Nanotechnology is a rapidly growing industry which promises tremendous scientific and economic potential. Engineered nanomaterial, nanoparticles have successfully drawn international attention owing to the novel physico-chemical properties they offer. Silver nanoparticles (Ag-np) currently have the highest degree of commercialization due to their anti-microbial potential (Ip et al, 2006), which made them component of wound-dressing, bandages, catheters, and plenty of other medical devices. Ag-np display longterm stability at room temperature in aqueous medium with small changes in morphology, shape, and size (Pinto et al, 2010). These properties are important for Ag-np to control their fate, transport, and bioavailability in both in vitro and in vivo models
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