Abstract 1774: Emerging role of Smad7 in DNA damage response pathway as a positive regulator.

Abstract The cellular response to DNA damage is essential in maintaining genomic stability. As DNA damage accumulates, the occurrence rate of cancer is significantly enhanced. Smad7 is known as an inhibitory Smad which negatively regulates TGF-β-induced signaling pathway. Smad7 is predominantly localized in the nucleus even without TGF-β stimulation. However, TGF-β-independent Smad7 function in the nucleus is still not clear. Here, we report Smad7 regulates DNA damage signaling in response to double-strand break induced by radiomimetic drug, neocarzinostatin (NCS). Smad7 overexpression accelerates DNA repair by enhancing phosphorylation of ATM and γH2AX, major DNA damage response signaling, after DNA damage. In Smad7−/− MEF cell, loss of Smad7 leads to failure of ATM phosphorylation and nuclear foci formation at the site of DNA damage upon NCS treatment. We show that Smad7 interacts with activated ATM/MRN complex and this interaction is significantly increased after DNA damage. Additionally, Smad7 co-localizes with pATM, MRN complex and γH2AX at the sites of DNA damage. Taken together, our data suggests that Smad7 plays a critical role in DNA damage response pathway through interaction with activated ATM. In this study, we reveal the de novo function of Smad7 in the nucleus. Citation Format: Sujin Park, Jin Muk Kang, Staci Jakyong Kim, Hyojung Kim, Seong-Jin Kim. Emerging role of Smad7 in DNA damage response pathway as a positive regulator. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1774. doi:10.1158/1538-7445.AM2013-1774