Abstract
Although the roles of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) in the non-homologous end joining (NHEJ) of DNA repair are well-recognized, the biological mechanisms and regulators by DNA-PKcs besides DNA repair, have not been clearly described. Here, we show that active DNA-PKcs caused by ionizing radiation, phosphorylated Snail1 at serine (Ser) 100, led to increased Snail1 stability. Furthermore, phosphorylated Snail1 at Ser100 reciprocally inhibited the kinase activity of DNA-PKcs, resulting in an inhibition of DNA repair activity. Moreover, Snail1 phosphorylation by DNA-PKcs was involved in genomic instability and aggressive tumor characteristics. Our results describe novel cellular mechanisms that affect genomic instability, sensitivity to DNA-damaging agents, and the migration of tumor cells by reciprocal regulation between DNA-PKcs and Snail1.
Highlights
The formation of DNA-PK complex by Ku70/80 and DNAPKcs, requires simultaneous binding of these enzymes to a DNA terminus.[2,3] After introduction of a double-strand breaks (DSBs), the DNA-PKcs enzyme is recruited rapidly to the DNA-Ku scaffold
Our preliminary study suggested that proteins that interact with Snail[1] included DNA-PKcs (Supplementary Figure S1)
The kinase activity of DNA-PKcs to phosphorylate p53 and histone H2AX is important for DNA repair activity, we examined whether binding of Snail[1] with DNA-PKcs affected this kinase activity of DNAPKcs
Summary
The formation of DNA-PK complex by Ku70/80 and DNAPKcs, requires simultaneous binding of these enzymes to a DNA terminus.[2,3] After introduction of a DSB, the DNA-PKcs enzyme is recruited rapidly to the DNA-Ku scaffold. Snail[1] was first described as a key regulator of the epithelial–mesenchymal transition (EMT) during development and in the progression of cancer, recent studies suggest that the aberrant expression of Snail[1] is involved in apoptotic resistance to various genotoxic agents including IR, as well as the acquisition of a stem cell phenotype.[6,7,8] recent evidence suggest that Snail[1] participates in both the EMT process and in the resistance to genotoxic stress, the molecular network of Snail[1] in the DNA repair process has not yet been identified. One of the proteins that interacts with Snail[1] was identified as DNA-PKcs. In this study, we demonstrated that a direct interaction between DNA-PKcs and Snail[1] induced phosphorylation of Snail[1] at serine (Ser) 100, resulting in Snail functional activity. The reciprocal regulation between DNA-PKcs and Snail[1] was critical for defective DNA repair activity, which affected genomic instability and the migration of tumor cells
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