Cell Line, Tumor ; Chromosome Aberrations/radiation effects ; DNA End-Joining Repair/radiation effects ; DNA-Activated Protein Kinase/antagonists & inhibitors ; DNA-Activated Protein Kinase/genetics ; DNA-Activated Protein Kinase/metabolism* ; Genomic Instability*/radiation effects ; Humans ; MCF-7 Cells ; Male ; Phosphorylation ; Protein Binding ; Protein Stability ; Protein Subunits/antagonists & inhibitors ; Protein Subunits/genetics ; Protein Subunits/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Radiation, Ionizing ; Snail Family Transcription Factors ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics ; Transcription Factors/metabolism*
Keywords
Cell Line, Tumor ; Chromosome Aberrations/radiation effects ; DNA End-Joining Repair/radiation effects ; DNA-Activated Protein Kinase/antagonists & inhibitors ; DNA-Activated Protein Kinase/genetics ; DNA-Activated Protein Kinase/metabolism* ; Genomic Instability*/radiation effects ; Humans ; MCF-7 Cells ; Male ; Phosphorylation ; Protein Binding ; Protein Stability ; Protein Subunits/antagonists & inhibitors ; Protein Subunits/genetics ; Protein Subunits/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Radiation, Ionizing ; Snail Family Transcription Factors ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics ; Transcription Factors/metabolism*
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.