Mutual regulation between DNA-PKcs and snail1 leads to increased genomic instability and aggressive tumor characteristics

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Authors: B-J Pyun ; H R Seo ; H-J Lee ; Y B Jin ; E-J Kim ; N H Kim ; H S Kim ; H W Nam ; J I Yook ; Y-S Lee

MeSH: 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.