FBXW7是SCF泛素连接酶的底物识别受体，通过促进多个原癌蛋白的K48泛素化降解来发挥肿瘤抑制功能。我们最近研究发现它也能介导XRCC4的K63泛素化促进非同源末端连接修复DNA损伤。但FBXW7是否发挥非蛋白泛素降解的功能和它在肺癌发生中的作用完全未知。我们前期工作表明FBXW7能与去甲基化酶LSD1结合，不促其降解，但影响各自的功能。本项目将1）首次揭示FBXW7具有非蛋白降解的全新功能，可通过与LSD1结合，影响LSD1去甲基化酶活性来参与表观遗传调控；而LSD1通过FBXW7的去甲基化来调控DNA修复；以非降解底物竞争性抑制FBXW7底物泛素化活性；2）运用基因敲除鼠肺癌模型证明FBXW7是肺的抑癌基因，而LSD1是促癌基因；3）运用临床样本证明FBXW7启动子超甲基化与其低表达和肺癌发生发展密切相关；FBXW7低表达可作为选择临床联用放化疗方案的标志物，具有潜在的转化应用价值。

FBXW7 is the substrate recognizing subunit of SCF (SKP1-Cullin-F-box protein) E3 ubiquitin ligase, and mainly known as a tumor suppressor by promoting ubiquitylation and degradation of oncogenic proteins (e.g. c-Myc, Notch, c-Jun, cyclin E) via K48-linked polyubiquitylation. Our recent study (Mol Cell 61: 419-433, 2016) showed that FBXW7 also promotes K63-linked polyubiquitylatoin of XRCC4 to facilitate non-homologous end-joining (NHEJ) repair. Whether FBXW7 has any ubiquitylation-independent function and its role in lung tumorigenesis are totally unknown. Here we showed that FBXW7 binds to LSD1, a protein demethylase, under physiological conditions, not for targeted ubiquitylation and degradation, but for functional modulation of each other. In this proposal, we will 1) show, for the first time, that FBXW7 indeed has ligase-independent function and elucidate mechanistically a) how FBXW7 is involved in epigenetic regulation via modulating LSD1 demethylase activity, and on the other hand, b) how LSD1 demethylates FBXW7 to regulate its NHEJ repair, and c) how LSD1, acting as a non-degradable pseudo-substrate, inhibits ligase activity of FBXW7 towards other real substrates; 2) use conditional KO in combination with KrasG12D-driven lung tumorigenesis model in mouse to demonstrate that Fbxw7 is a tumor suppressor, whereas LDS1 promotes tumorigenesis in the lung; 3) use clinical lung cancer tissues to show that hyper-methylation in the promoter of FBXW7 gene is responsible for its reduced expression, and FBXW7 down-regulation is associated with better patient response to chemoradiation therapy due to reduced NHEJ repair. Thus, FBXW7 level can serve as an efficacy biomarker. Our study, ranging from basic research to animal models, then to clinical study, not only elucidates mechanistically the novel functions of FBXW7-LSD1 in regulation of epigenetics, DNA damage repair, and lung tumorigenesis, but also has significant translational potential in precision medicine for individual based effective cancer therapy as well as for patient prognosis.