The role of atypical ubiquitin chains in intestinal homeostasis and colorectal cancer

Abstract

Ubiquitination is a post-translational modification that is essential for protein regulation in the cell and is involved in virtually all cellular processes. Although ubiquitination has been studied for more than 40 years, there are still many unknowns, including the role of atypical ubiquitin chains, a type of ubiquitin modification that is underrepresented in cells. The functions of these atypical chains, the physiological and pathological processes involved, and the underlying molecular mechanisms are still poorly characterized. In this Ph.D. project, I aim to narrow this knowledge gap by studying Trabid, a deubiquitinating enzyme specific for atypical ubiquitin chains, and whose own functions remain enigmatic. Our first studies characterizing Trabid-deficient mice suggested that Trabid, and in turn, most likely, atypical ubiquitin chains, could be involved in the regulation of the intestinal Stem cell niche. Intestinal Stem cells are important for intestinal homeostasis, being involved not only in the renewal of intestinal epithelial cells under physiological conditions but also in the repair of intestinal damage. In addition, pathological hyperplasia of intestinal Stem cells can lead to the development of colorectal cancer. Thus, this Ph.D. project is of relevance not only for the ubiquitin field but also for regenerative and cancer therapies.