caa a22 4500 606175938 CHVBK 20210128100745.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s00018-014-1687-z doi (NATIONALLICENCE)springer-10.1007/s00018-014-1687-z Smad7 enhances ATM activity by facilitating the interaction between ATM and Mre11-Rad50-Nbs1 complex in DNA double-strand break repair [Elektronische Daten] [Sujin Park, Jin Kang, Staci Kim, Hyojung Kim, Suntaek Hong, Young Lee, Seong-Jin Kim] Genomic instability is one of the representative causes in genetic disorder, where the proper cellular response to DNA damage is essential in maintaining genomic stability. ATM and the Mre11-Rad50-Nbs1 (MRN) complex play critical roles in the cellular response to DNA damage such as DNA double-strand break (DSB). In this study, we report that Smad7 is indispensible in DNA damage response as a novel component of MRN complex. Smad7 enhances cell survival against DNA damage by accelerating ATM dependent DNA repair signaling. In Smad7-deficient mouse embryonic fibroblast cells, the loss of Smad7 decreases ATM activation and inhibits recruitment of ATM to the sites of DSBs. Smad7 interacts with Nbs1, a member of MRN complex, and enhances the interaction between ATM and Nbs1 upon DNA damage response, leading to phosphorylation of downstream substrates. Ectopic expression of Smad7 in the skin of mice enhances the phosphorylation of ATM upon X-irradiation. We found that effect of Smad7 on enhancing DNA repair is independent of its inhibitory activity of TGF-β signaling. Taken together, our results highlight a critical function of Smad7 in DSB response and establish the novel mechanism in which Smad7 facilitates the recruitment of ATM to the MRN complex through direct interaction with Nbs1. Springer Basel, 2014 Carcinogenesis nationallicence DNA damage response (DDR) nationallicence DNA damage checkpoint nationallicence Genotoxic stress nationallicence Neocarzinostatin (NCS) nationallicence Park Sujin CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut Kang Jin CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut Kim Staci CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut Kim Hyojung CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut Hong Suntaek Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 406-840, Incheon, Republic of Korea aut Lee Young Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 406-840, Incheon, Republic of Korea aut Kim Seong-Jin CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut Cellular and Molecular Life Sciences Springer Basel 72/3(2015-02-01), 583-596 1420-682X 72:3<583 2015 72 18 https://doi.org/10.1007/s00018-014-1687-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1687-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Park Sujin CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut NATIONALLICENCE 700 1- Kang Jin CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut NATIONALLICENCE 700 1- Kim Staci CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut NATIONALLICENCE 700 1- Kim Hyojung CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut NATIONALLICENCE 700 1- Hong Suntaek Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 406-840, Incheon, Republic of Korea aut NATIONALLICENCE 700 1- Lee Young Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 406-840, Incheon, Republic of Korea aut NATIONALLICENCE 700 1- Kim Seong-Jin CHA Cancer Institute, CHA University, 135-081, Seoul, Republic of Korea aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/3(2015-02-01), 583-596 1420-682X 72:3<583 2015 72 18