The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes. Both genetic and epigenetic alterations account for the deregulation of E3s in cancer. Consequently, the stability and/or activity of E3 substrates are also altered, in some cases leading to downregulation of tumour-suppressor activities and upregulation of oncogenic activities. A better understanding of the mechanisms underlying E3 regulation and function in tumorigenesis is expected to identify novel prognostic markers and to enable the development of the next generation of anticancer therapies. This Review summarizes the oncogenic and tumour-suppressor roles of selected E3s and highlights novel opportunities for therapeutic intervention.

细胞对外部应激信号和DNA损伤的反应取决于泛素连接酶（E3s）的活性，该酶调节多种细胞过程，包括体内平衡，代谢和细胞周期进程。E3以时间和空间调节的方式识别，相互作用并泛素化蛋白质底物。泛素链的拓扑结构决定了底物的命运，标志着它们被蛋白酶体识别或降解，或者改变其亚细胞定位或组装成功能复合物。遗传和表观遗传改变都解释了癌症中E3的失控。因此，E3底物的稳定性和/或活性也被改变，在某些情况下导致肿瘤抑制活性的下调和致癌活性的上调。更好地了解肿瘤发生中E3调控和功能的基本机制有望鉴定出新的预后标志物，并使下一代抗癌疗法得以发展。这篇综述总结了所选E3的致癌作用和抑癌作用，并强调了治疗干预的新机会。