Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal control of key molecules during each of these important cellular processes. Loss of precision results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.

哺乳动物的发育需要精确。数以百万计的分子必须按时间顺序正确定位，并对其功能进行调节，以协调细胞周期进程、细胞凋亡、迁移和分化中的重要步骤，从而塑造发育中的胚胎。泛素及其相关酶充当细胞守护者，以确保在每个重要的细胞过程中对关键分子进行精确的时空控制。精确度的损失会导致许多胚胎疾病甚至癌症的例子。本综述讨论了 E3 泛素连接酶在哺乳动物早期发育的关键步骤中的关键作用及其在人类疾病中的作用，并考虑了如何操纵和利用泛素调节机制的新方法——例如，