阐明肿瘤细胞衰老及其逃逸的机制是理解三阴性乳腺癌发生与演进、化疗抵抗、探索协同治疗新策略的重要基础。我们前期发现泛素连接酶SKP2缺失加速细胞衰老，增强阿霉素对细胞的杀伤性，但机制不清；进一步证据表明SKP2和ATAD3A相互作用，是ATAD3A的泛素连接酶，抑制ATAD3A二聚体形成增强PINK1表达。本项目提出“SKP2介导ATAD3A泛素化激活PINK1依赖性线粒体自噬，从而使肿瘤细胞逃避衰老的命运，导致化疗抵抗”的假说，拟采用体内体外泛素化实验、Co-IP、 基因定点突变等技术明确SKP2-ATAD3A-PINK1线粒体自噬途径在肿瘤细胞衰老逃逸和阿霉素化疗抵抗中的关键作用，揭示SKP2泛素化ATAD3A激活PINK1依赖性线粒体自噬的分子机制及临床学意义；结果可望为深入认识肿瘤衰老逃逸的源动力机制和探索三阴性乳腺癌协同治疗新策略提供新思路和靶点。

Clarifying the mechanism of tumor cell senescence escape is important for understanding the initiation, progression and chemotherapy resistance of triple-negative breast cancer, and to investigate the novel synergistic strategy for cancer treatment. Our preliminary data showed that the loss of ubiquitin ligase SKP2 accelerated cellular senescence and increased the cytotoxicity of doxorubicin. However, the detailed mechanism remains unclear. Further evidence suggested that SKP2 interacted with ATAD3A and served as the ubiquitin ligase of ATAD3A. SKP2 inhibited the formation of ATAD3A homodimer, and promoted the expression of PINK1. Herein we proposed that SKP2 mediates ATAD3A ubiquitination to activate PINK1-dependent mitophagy, leading to senescence evasion and chemotherapy resistance. Multiple molecular techniques including in vivo/in vitro ubiquitination assay, Co-IP, and gene mutagenesis will be applied to decipher the critical role of SKP2-ATAD3A-PINK1 mitophagy pathway in tumor cell senescence evasion and chemotherapy resistance, and to reveal the molecular mechanism and clinical significance of SKP2-mediated ATAD3A ubiquitination and PINK1-dependent mitophagy activation. The results may not only provide the further understanding of the driving mechanism of tumor senescence evasion, but also provide insights and targets for developing novel therapeutic strategies.