Cancer is a multifaceted disease in which dysregulated gene expression and other aberrant activities are crucial for neoplastic initiation, progression and tumor cell survival upon the treatment with anticancer modalities.One of the major mechanisms that regulate these processes is protein ubiquitination. This modification can impose diverse effects on gene products–proteins, ranging from proteolysis to modulation of protein structure, localization and function. Central components of ubiquitination are the E3 ubiquitin ligases (E3s). Among the different types of E3s, HECT-type E3 ligases are largely unexplored. Recently, the anticancer roles of these enzymes have become highly relevant as we discovered prominent tumor-suppressor functions of one member of this family – Smurf2 (Blank M et al., Nature Med 2012). However, many gaps still remain in our understanding of Smurf2 biological functions in cancer, and potentially important therapeutic targets are missed.The main objective of our research is to delineate the spectrum of molecular mechanisms operating in the cell under the jurisdiction of Smurf2, focusing primarily on those involved in the regulation of chromatin organization and dynamics, gene expression, DNA damage repair and genomic integrity maintenance. They are all interconnected and often compromised in cancer pathways. Using multidisciplinary approaches spanning these areas, we are determined to shed light on roles that HECT-type E3 ligases in general and Smurf2 in particular play in tumor biology and, more importantly, the sensitivity of cancer cells to DNA damage-inducing therapies. Together with surgery, these comprise current first choice in cancer treatment. We believe that the knowledge generated by this study has the potential to provide novel targets in cancer treatment and the design of new, more efficient, therapeutics to combat this devastating disease.