Nico Dantuma's Group
Our major objectives are to understand the role of the ubiquitin/proteasome system in the development of neurodegenerative diseases and cancer and to explore the therapeutic potential of modifiers of this system.
Regulated degradation of proteins in our cells is executed by the ubiquitin/proteasome system. As such the ubiquitin/proteasome system is critical for the degradation of key regulators that are implicated in signaling, regulation of the cell cycle and induction of apoptosis. Moreover, the ubiquitin/proteasome system is also important for protein quality control given its role in the destruction of abnormal, misfolded and dysfunctional proteins. Hundreds of enzymes are involved in the coordinated efforts of the ubiquitin/proteasome system in protein degradation underscoring its potential as therapeutic target for a broad variety of diseases. Tumor cells are in particularly sensitive to inhibition of the ubiquitin/proteasome system and the first proteasome inhibitor has recently been introduced in the clinic for the treatment of multiple myeloma, a type of blood cancer. Interestingly, enhancing proteasomal degradation of proteins linked to neurodegenerative diseases can reduce their toxicity.
We have developed tools to study the ubiquitin/proteasome system in cellular and animal models. Real-time imaging of fluorescently tagged proteins in living cells plays an important role in our research. These experimental approaches are used to gain insights in the functional status of the ubiquitin/proteasome system in various diseases and to decipher the molecular mechanisms that are responsible for alterations caused by disease-associated proteins. In addition, we use these models in the development of novel compounds that target the ubiquitin/proteasome system. We are also exploring the non-proteolytic role of ubiquitin in the cellular response to DNA damage.
|Tatiana Alvarez Giovannucci||PhD student|
|Laura Herzog||PhD student, Graduate Student|
|Annika Pfeiffer||PhD student, Graduate Student|
|Thibaud Richard||Graduate Student|
|Florian Salomons||Senior lab manager|
|Shanshan Xu||PhD student, Student|
The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks.
Nat. Struct. Mol. Biol. 2011 Nov;18(12):1345-50
C-terminal UBA domains protect ubiquitin receptors by preventing initiation of protein degradation.
Nat Commun 2011 Feb;2():191
Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment.
Proc. Natl. Acad. Sci. U.S.A. 2009 Aug;106(33):13986-91
The UBA2 domain functions as an intrinsic stabilization signal that protects Rad23 from proteasomal degradation.
Mol. Cell 2005 Apr;18(2):225-35
A transgenic mouse model of the ubiquitin/proteasome system.
Nat. Biotechnol. 2003 Aug;21(8):897-902