基因组DNA双链断裂（DSB）非同源性末端连接（NHEJ）修复与基因组稳定性、肿瘤发生及放化疗敏感性密切相关。我们前期研究发现E3泛素连接酶CUL4A具有抑制DSB损伤修复的作用，能通过其底物识别受体DTL结合并泛素化降解NHEJ核心组分DNA-PKcs，提示CUL4A通过DTL靶向降解DNA-PKcs抑制DSB损伤的NHEJ修复、增加基因组不稳定性，从而增加肿瘤易感性，但其在肿瘤发生中的确切分子机制及生物学意义尚需进一步明确与核实。为此，本项目拟通过细胞DNA损伤模型、相应的分子细胞生物学技术、转基因及基因敲除小鼠成瘤模型和临床标本分析CUL4A调控DNA-PKcs的作用和机理，明确CUL4A-DTL-DNA-PKcs通路抑制DSB损伤NHEJ修复的作用及其在肿瘤发生中的生物学和临床意义。本项目的顺利实施将有助于更好地理解CUL4A在肿瘤发生中的作用及机制，为肿瘤防治提供新的理论基础。

Nonhomologous end-joining (NHEJ) repair of genomic DNA double-strand breaks (DSBs) is closely related to genomic instability, tumor genesis, development and chemo-radiotherapy sensitivity. Our previous study showed that E3 ubiquitin ligase CUL4A could inhibit the repair of DSB injury. Further investigation indicated that CUL4A could interact with DNA-PKcs, a core component of NHEJ machinery, through DTL, one of the substrate receptors of CUL4A E3 ligase complex, and degrade DNA-PKcs in an ubiquitin dependent proteasome pathway. Our preliminary data suggested that CUL4A can inhibit NHEJ repair of DNA DSB lesions and possibly increase the genomic DNA instability and the subsequent cancer susceptibility through regulating DNA-PKcs protein level. However, its exact function, underlying molecular mechanisms and the consequent biological and clinical significances in tumorigenesis need further investigation and validation. Therefore, this project intends to analyze the regulatory effect of CUL4A on DNA-PKcs, related molecular mechanism and the biological and clinical implications of CUL4A-DTL-DNA-PKcs pathway in tumorigenesis through DNA DSB damage model, molecular and cell biological techniques, transgenic and gene knockout mouse models and patients' samples. The successful implementation of this project will help to better understand the mechanistic roles of CUL4A in tumorigenesis and provide a theoretical basis for the prevention and intervention of tumorigenesis.