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 play a role in cancer. Here, we uncovered the landscape of the contribution of such alterations to tumorigenesis across cancer types. We first systematically identified novel instances of degrons across the human proteome using a random forest classifier, and validated them exploiting somatic mutations across more than 7,000 tumors. We detected signals of positive selection across these novel degrons and revealed new instances involved in cancer development. Overall, we estimated that at least one in seven driver mutations across primary tumors affect either degrons or E3 ligases.

Disruption of ubiquitin mediated proteolysis is a widespread mechanism of tumorigenesis