TGF-β1 accelerates the DNA damage response in epithelial cells via Smad signaling

• Published in: Biochemical and biophysical research communications Vol. 476; no. 4; pp. 420 - 425
• Main Authors: Lee, Jeeyong, Kim, Mi-Ra, Kim, Hyun-Ji, An, You Sun, Yi, Jae Youn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.08.2016
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; APOPTOSIS; BIOLOGICAL PATHWAYS; BIOLOGICAL REPAIR; Cell Line; DNA; DNA Damage - drug effects; DNA Damage - radiation effects; DNA damage response; DNA DAMAGES; DNA Ligase ATP - metabolism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - radiation effects; Female; Gamma Rays; GROWTH FACTORS; HISTONES; Humans; IN VIVO; IRRADIATION; Lig4; LIGASES; Mice, Nude; Radioprotection; RECEPTORS; Signal Transduction - drug effects; Signal Transduction - radiation effects; SIGNALS; Smad Proteins - genetics; Smad Proteins - metabolism; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Smad3 Protein - metabolism; Smads; TGF-β1; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - pharmacology; Xenograft Model Antitumor Assays; TGF-β1; Smads; DNA damage response; Radioprotection; Lig4
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.05.136

The evidence suggests that transforming growth factor-beta (TGF-β) regulates the DNA-damage response (DDR) upon irradiation, and we previously reported that TGF-β1 induced DNA ligase IV (Lig4) expression and enhanced the nonhomologous end-joining repair pathway in irradiated cells. In the present study, we investigated the effects of TGF-β1 on the irradiation-induced DDRs of A431 and HaCaT cells. Cells were pretreated with or without TGF-β1 and irradiated. At 30 min post-irradiation, DDRs were detected by immunoblotting of phospho-ATM, phospho-Chk2, and the presence of histone foci (γH2AX). The levels of all three factors were similar right after irradiation regardless of TGF-β1 pretreatment. However, they soon thereafter exhibited downregulation in TGF-β1-pretreated cells, indicating the acceleration of the DDR. Treatment with a TGF-β type I receptor inhibitor (SB431542) or transfections with siRNAs against Smad2/3 or DNA ligase IV (Lig4) reversed this acceleration of the DDR. Furthermore, the frequency of irradiation-induced apoptosis was decreased by TGF-β1 pretreatment in vivo, but this effect was abrogated by SB431542. These results collectively suggest that TGF-β1 could enhance cell survival by accelerating the DDR via Smad signaling and Lig4 expression. •TGF-β1 pretreatment accelerates γ-radiation-induced DNA damage response.•TGF-β1-accelerated DNA damage response is dependent on Smad signaling and DNA Ligase IV.•TGF-β1 pretreatment protects epithelial cells from γ-radiation in vivo.