E3 ligases and degrons, the sequences they recognize in target proteins, are key parts of the ubiquitin-mediated proteolysis system. There are several examples of alterations of these two components of the system that have a role in cancer. Here we uncover the landscape of the contribution of such alterations to tumorigenesis across cancer types. We first systematically identified new instances of degrons across the human proteome by using a random forest classifier and validated the functionality of a dozen of them, exploiting somatic mutations across >7,000 tumors. We detected signals of positive selection across known and new degron instances. Our results reveal that several oncogenes are frequently targeted by mutations that affect the sequence of their degrons or their cognate E3 ubiquitin ligases, causing an abnormal increase in their protein abundance. Overall, an important number of driver mutations across primary tumors affect either degrons or E3-ubiquitin ligases.

E3 连接酶和 degrons，它们在靶蛋白中识别的序列，是泛素介导的蛋白水解系统的关键部分。有几个例子表明系统的这两个组成部分在癌症中起作用。在这里，我们揭示了这种改变对不同癌症类型的肿瘤发生的贡献。我们首先通过使用随机森林分类器系统地识别了人类蛋白质组中的 degrons 新实例，并验证了其中十几个的功能，利用了超过 7,000 个肿瘤的体细胞突变。我们在已知和新的 degron 实例中检测到正选择信号。我们的研究结果表明，一些癌基因经常被影响其 degrons 或其同源 E3 泛素连接酶序列的突变所靶向，导致它们的蛋白质丰度异常增加。总体而言，原发性肿瘤中的大量驱动突变会影响 degrons 或 E3-泛素连接酶。