Hong, XuehuiLiu, WenyuSong, RuipengShah, Jamie J.Feng, XingTsang, Chi KwanMorgan, Katherine M.Bunting, Samuel F.Inuzuka, HiroyukiZheng, X. F. StevenShen, ZhiyuanSabaawy, Hatem E.Liu, LianXinPine, Sharon R.2016-11-182016Hong, X., W. Liu, R. Song, J. J. Shah, X. Feng, C. K. Tsang, K. M. Morgan, et al. 2016. “SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.” Nucleic Acids Research 44 (18): 8855-8869. doi:10.1093/nar/gkw748. http://dx.doi.org/10.1093/nar/gkw748.0305-1048http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408141SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis and progression of human tumors by increasing cell proliferation and epithelial-mesenchymal transition. We found that in response to UV irradiation or genotoxic chemotherapeutics, SOX9 is actively degraded in various cancer types and in normal epithelial cells, through a pathway independent of p53, ATM, ATR and DNA-PK. SOX9 is phosphorylated by GSK3β, facilitating the binding of SOX9 to the F-box protein FBW7α, an E3 ligase that functions in the DNA damage response pathway. The binding of FBW7α to the SOX9 K2 domain at T236-T240 targets SOX9 for subsequent ubiquitination and proteasomal destruction. Exogenous overexpression of SOX9 after genotoxic stress increases cell survival. Our findings reveal a novel regulatory mechanism for SOX9 stability and uncover a unique function of SOX9 in the cellular response to DNA damage. This new mechanism underlying a FBW7-SOX9 axis in cancer could have implications in therapy resistance.en-USJournal Article2016-11-1810.1093/nar/gkw748