Nico Dantuma's Group (»Add to Infobox)

von Eulers väg 3 17177 Stockholm Phone:  0046-852487384 Fax:  0046-8-313529 Internet:  http://www.cmb.ki.se/research/dantuma/index.html

General description: The research in our laboratory focuses on two important aspects of the ubiquitin/proteasome system (UPS): 1.  The functional status of the UPS in neurodegenerative disorders 2.  The role of the UPS in nucleotide excision repair Central in both research projects is the question why certain proteasome substrates resist proteasomal degradation. A number of studies suggest that dysfunction of the UPS may be an important determinant for the development of neurodegenerative disorders. We have developed a number of unique tools to study various aspects of the UPS in living cells and in mice. Recently we reported that conditions of proteotoxic stress compromises the functionality of the UPS. In our ongoing work, we are analyzing the behaviour of ubiquitin-dependent processes together with other processes involved in the clearance of misfolded proteins using live cell imaging. We will also study in more detail the unique interaction between the proteasome and UBB+1, an aberrant form of ubiquitin that is found in Alzheimer’s disease, in order to understand why this substrate frustrates proteasomal degradation. Nucleotide excision repair (NER) is the repair machinery that is involved in removing UV-induced DNA damage. Patients that have a deficient NER system due to genetic aberrations suffer from the repair syndrome xeroderma pigmentosum (XP) causing hypersensitivity to sunlight and predisposition to the development of cancer. We found that the DNA repair protein Rad23 resists proteasomal degradation. This protective effect is mediated through its C terminal ubiquitin associated domain (UBA). Moreover, we reported that UV exposure causes a profound and long lasting NER-dependent ubiquitylation of histone H2A, a novel UV induced histone modficiation with unknown significance in NER. We are presently investigating the molecular mechanisms and functional significance of these phenomena that link the UPS to DNA repair. For this purpose, we will use a number of approaches including genome-wide screens in yeast, real-time imaging of DNA repair in living cells and biochemical assays. Moreover, the first compound that block the proteolytic activity of the proteasome has been recently introduced in the clinic for treatment of multiple myleoma. Our UPS reporter mice will be used to develop and characterize novel inhibitors.		Living cells expressing YFP reporter substrate of UPS

MEMBERS (10/10)

Dantuma Nico, Associate Professor (Principal Investigator / Nico Dantuma's Group)