The evidence suggests that transforming growth factor-beta (TGF-beta) regulates the DNA-damage response (DDR) upon irradiation, and we previously reported that TGF-beta 1 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-beta 1 on the irradiation-induced DDRs of A431 and HaCaT cells. Cells were pretreated with or without TGF-beta 1 and irradiated. At 30 min post-irradiation, DDRs were detected by immunoblotting of phospho-ATM, phospho-Chk2, and the presence of histone foci (gamma H2AX). The levels of all three factors were similar right after irradiation regardless of TGF-beta 1 pretreatment. However, they soon thereafter exhibited downregulation in TGF-beta 1-pretreated cells, indicating the acceleration of the DDR. Treatment with a TGF-beta 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-beta 1 pretreatment in vivo, but this effect was abrogated by SB431542. These results collectively suggest that TGF-beta 1 could enhance cell survival by accelerating the DDR via Smad signaling and Lig4 expression. (C) 2016 Elsevier Inc. All rights reserved.