Ubiquitination and ubiquitin-like (UbL) modifications regulate virtually all cellular pathways, including those relevant for cancer cell proliferation and genome integrity such as the DNA damage response and DNA replication. The ubiquitin system is particularly attractive as anticancer target, thanks to the presence of specific enzymatic – and therefore "druggable" – activities modulating different aspects of DNA metabolism. Inhibiting key ubiquitin-related DNA repair factors could potentiate commonly used anticancer drugs that induce genotoxic stress. However, reaching this goal requires molecular understanding of the ubiquitin-mediated control of genome stability in various conditions of stress. Our research aims to understand how cells exploit the ubiquitin and UbL systems to react to endogenous and exogenous genotoxic stress, and how these signals are decoded into functional outputs.