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.

Microscopic picture of a neuronal cell

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.

Group members

Sebastian Meister, Maria Gierisch, Daniel Iglesias van Montfort, Shanshan Xu, Florian Salomons, Nico Dantuma, Chris Braganca.

Selected publications

Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound.
Giovannucci TA, Salomons FA, Haraldsson M, Elfman LHM, Wickström M, Young P, Lundbäck T, Eirich J, Altun M, Jafari R, Gustavsson AL, Johnsen JI, Dantuma NP
Cell Death Dis 2021 10;12(10):914

The Machado-Joseph disease deubiquitylase ataxin-3 interacts with LC3C/GABARAP and promotes autophagy.
Herzog LK, Kevei É, Marchante R, Böttcher C, Bindesbøll C, Lystad AH, Pfeiffer A, Gierisch ME, Salomons FA, Simonsen A, Hoppe T, Dantuma NP
Aging Cell 2020 01;19(1):e13051

Ataxin-3 consolidates the MDC1-dependent DNA double-strand break response by counteracting the SUMO-targeted ubiquitin ligase RNF4.
Pfeiffer A, Luijsterburg MS, Acs K, Wiegant WW, Helfricht A, Herzog LK, et al
EMBO J. 2017 04;36(8):1066-1083

The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks.
Acs K, Luijsterburg MS, Ackermann L, Salomons FA, Hoppe T, Dantuma NP
Nat. Struct. Mol. Biol. 2011 Nov;18(12):1345-50

Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment.
Maynard CJ, Böttcher C, Ortega Z, Smith R, Florea BI, Díaz-Hernández M, et al
Proc. Natl. Acad. Sci. U.S.A. 2009 Aug;106(33):13986-91

DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A.
Bergink S, Salomons FA, Hoogstraten D, Groothuis TA, de Waard H, Wu J, Yuan L, Citterio E, Houtsmuller AB, Neefjes J, Hoeijmakers JH, Vermeulen W, Dantuma NP
Genes Dev 2006 May;20(10):1343-52

Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells.
Dantuma NP, Lindsten K, Glas R, Jellne M, Masucci MG
Nat Biotechnol 2000 May;18(5):538-43