单泛素化NEMO网络失控促DNA损伤炎症诱发恶性转化的分子机制

DNA损伤诱发的炎性既可诱导细胞衰老而抑制肿瘤发生也可增强抗凋亡能力而诱发肿瘤。但炎性通路同时抑癌/促癌的关键节点及调控机制仍不清楚。我们前期发现泛素化酶TRIM37单泛素化的NEMO在DNA损伤细胞中即是激活NFκB炎症通路也是调控超级增强子决定细胞命运的关键节点。进一步预实验表明单泛素化NEMO可结合组蛋白H1F0及超保守非编码RNA:①募集NFκB因子转录上调促炎因子而维持细胞高炎性；②招募JDP2等转录因子上调p16INK4a/ARF而促进细胞衰老；③去泛素化酶USP10负反馈去除NEMO单泛素化而抑制炎症强度；④DNA损伤成纤维细胞通过NFκB炎症通路而诱导分泌WNT16B等多种因子形成促恶性转化的微环境。⑤TCGA分析显示多种肿瘤早期已表现出高程度的TRIM37扩增及JDP2/USP10缺失。本项目将承前启后，深层次解析单泛素化NEMO网络失控促DNA损伤炎症诱发肿瘤的新机制。

It has been widely accepted that the inflammation induced by DNA damage plays vital roles in promoting cell senescence, which is a functional barrier to carcinogenesis, but also in enhancing the anti-apoptotic capability of DNA damaged cells, which may promote transformation. However, the regulatory mechanisms and the key factors that contribute to functional conversion of tumor suppressor and tumorigenesis are still largely unclear. Previously, we found that ubiquitinase TRIM37 mediated NEMO mono-ubiquitination is the key factors for DNA damage-activated NF-κB inflammatory signaling pathway. Surprisingly, we also found that mono-ubiquitinated NEMO could also interact with the super enhancer and regulates multiple genes that determine the fate of DNA damaged cells. Furthermore, we demonstrated that experiments show that mono-ubiquitinated NEMO could bind to histone H1F0 and ultraconserved noncoding RNA (ucRNA), which:① specifically upregulated several proinflammatory cytokines through recruitment of NF-κB transcription factor, which kept cells in chronic inflammatory states; ② transcriptional upregulated p16INK4a/ARF locus via recruitment of JDP2 and Nkx2-8 transcription factors, which induced cell senescence; And the deubiquitinase USP10 could negatively inhibit DNA damage-activated NF-κB signaling via removal of mono-ubiquitination; Meanwhile, the DNA damaged-fibroblasts established a tumor microenvironment via secreting amount of cytokines, such as WNT16B, which can significantly enhanced the transformation efficiency of TRIM37/JDP2-/-/USP10-/- cells. Therefore, the current project utilized in vivo and in vitro experimental systems combined with data from clinical samples to investigate the mechnisam by which dysregulated network of NEMO monoubiquitination on genotoxic inflammation-induced transformation.