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Smad7 enhances ATM activity by facilitating the interaction between ATM and Mre11-Rad50-Nbs1 complex in DNA double-strand break repair

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Abstract

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.

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Acknowledgments

The authors would like to thank Wang, XJ for the K7.Smad7 transgenic mice and Yoon, K, Choi, CY, and Kim, TK for technical support. This work was supported by Basic Science Research Program (NRF 2011-0014281) and the Bio-Synergy Research Project (NRF-2012M3A9C4048735) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea (NRF).

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All authors declare that they have no competing interests.

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Authors and Affiliations

  1. CHA Cancer Institute, CHA University, Seoul, 135-081, Republic of Korea

    Sujin Park, Jin Muk Kang, Staci Jakyong Kim, Hyojung Kim & Seong-Jin Kim

  2. Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea

    Suntaek Hong & Young Jae Lee

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  1. Sujin Park
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Park, S., Kang, J.M., Kim, S.J. et al. Smad7 enhances ATM activity by facilitating the interaction between ATM and Mre11-Rad50-Nbs1 complex in DNA double-strand break repair. Cell. Mol. Life Sci. 72, 583–596 (2015). https://doi.org/10.1007/s00018-014-1687-z

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