The Svedberg Award 2007
Nico Dantuma
Department of Cell and Molecular Biology (CBM), Karolinska Institutet
Background
In 1992, I graduated in Biology and Medical Biology at the Free
University in Amsterdam. As part of my undergraduate training, I had
spent already more than one year at the bench being involved in two
research projects dealing with enteropathogenic bacteria and
estrogen-dependent growth of breast tumors at the Free University and
the Netherlands Cancer Institute, respectively. It was during this time
at the bench that I became really fascinated with science and in
particular with doing research. Directly after my graduation, I started
my PhD project at the Utrecht University where I studied how the
African migratory locust (Locusta migratoria) mobilizes and transports
lipids during their long distance flights resulting in the
identification of a novel endocytotic lipoprotein receptor. In 1997, I
defended my thesis and moved to Stockholm to join the laboratory of
Maria Masucci, who was then at Microbiology and Tumor Biology center
(MTC) of the Karolinska Institute. It was in the Masucci lab that I
started to work on the ubiquitin/proteasome system, which is still the
major focus of our research. As a postdoctoral fellow I studied how the
Epstein Barr virus, which causes infectious mononucleosis and is linked
to several forms of cancer, manipulates the ubiquitin/proteasome
system. After my postdoctoral period, I established my own research
group with a major focus on the ubiquitin/proteasome system in
neurodegenerative disorders such as Alzheimer’s, Parkinson’s and
Huntington’s disease. In 2003, I spent a sabbatical year in the group
of Jacques Neefjes at the Netherlands Cancer Institute during which I
became acquainted with various live cell imaging techniques. Shortly
after my return to Stockholm, I moved my group to the department of
Cell and Molecular Biology (CMB) also at the Karolinska Institute,
where we continued our work on the ubiquitin/proteasome system in
neurodegeneration as well as the development of new tools for following
the ubiquitin/proteasome system in living cells. More recently, we
started to study the role of the ubiquitin/proteasome system in DNA
repair, a process that is highly relevant for our understanding of
cancer.
Research
The ubiquitin/proteasome system is involved in many cellular processes.
It is for example important for the cell cycle, programmed cell death,
transcription, DNA repair, intracellular transport and, last but not
least, for the destruction of misfolded or otherwise abnormal proteins.
Best known is the role of the ubiquitin/proteasome system in regulated
degradation of proteins but it also has less well understood
non-proteolytic functions. Degradation is accomplished in a two step
process. First, proteins that are destined for degradation are
poly-ubiquitylated, which means that a long chain of a small protein
called ubiquitin is being attached to the protein that will be
degraded. Second, proteins with poly-ubiquitin chains bind to the
proteasome, which is a large proteolytic complex that subsequently cuts
the poly-ubiquitylated protein in small fragments. Regulated
degradation of proteins is the perfect means to irreversibly inactivate
regulatory proteins or to destroy abnormal and potentially dangerous
proteins. It has become increasingly clear that there are different
forms of ubiquitylation and many of those do not target proteins for
degradation. For example, in transcription and DNA repair
mono-ubiquitylation (attachment of a single ubiquitin) plays an
important regulatory role without targeting proteins for degradation.
We have developed a number of tools that allows to analyse the
functionality of the ubiquitin/proteasome system and to follow the
dynamics of certain components of the system. Many neurodegenerative
diseases are characterized by the presence of deposits of aggregated
misfolded proteins in the affected brain regions. Since the
ubiquitin/proteasome system is the primary pathway responsible for
clearance of misfolded proteins, it has been proposed that problems
with the ubiquitin/proteasome system may be a common nominator in
neurodegenerative disorders. With our tools we have, for example, shown
that protein aggregation causes a major problem for the system. We also
found that an abnormal ubiquitin which has been found in Alzheimer’s
disease interferes with the household functions of the
ubiquitin/proteasome system. Finally, we demonstrated that cellular
stress conditions, which are commonly found in neurodegenerative
diseases, affects the functionality of the ubiquitin/proteasome system.
We have been trying to elucidate why the ubiquitin/proteasome system
works less efficient during stress conditions. To our surprise, we
found that probably the protein ubiquitin itself is the bottleneck.
Despite the fact that high levels of ubiquitin are present in all
cells, the levels are still rate limiting which is probably due to the
fact that ubiquitylation is involved in so many cellular processes. As
a consequence different ubiquitin-dependent processes are competing for
a limited pool of ubiquitin and especially during stress when much more
ubiquitin is required for degradation the system runs havoc. Based on
this finding we postulated the ‘ubiquitin equilibrium hypothesis’
according to which the limited amount of ubiquitin enables crosstalk
between various ubiquitin-dependent processes. We indeed found that
blocking ubiquitin-dependent degradation directly affects
ubiquitin-dependent transcription by competing ubiquitin from histones
which dictate transcriptional activity. At the moment, we are also
looking at other ubiquitin-dependent processes to get a better idea of
the level of crosstalk and the relevance if this crosstalk in diseases.
Inspired by our earlier work in which we studied how certain proteins
resist proteasomal degradation, we started to work on Rad23, a protein
involved in nucleotide excision repair which protects our genome from
UV-induced DNA damage. Interestingly, Rad23 has to interact with the
proteasome when the DNA is being repaired but somehow it escapes from
degradation. We identified the domain (stabilization signal) that is
responsible for protecting Rad23 and showed that the stabilization
signal of Rad23 is important for DNA repair. Thus, our research shows
that some proteins protect themselves from degradation by the
proteasome, a situation that we had only observed previously for
pathologic proteins such as a viral protein and proteins causing
neurodegenerative diseases. We also found that UV light causes
mono-ubiquitylation of histones and that this is ubiquitylation is part
of the DNA repair response, which is another example of the direct link
between DNA repair and the ubiquitin/proteasome system. The functional
significance of this DNA damage-induced histone modification remains
unclear.
In our ongoing research, we focus on these fascinating aspects of the
ubiquitin/proteasome system and are ready for new surprises.
Please visit our website for more information:
Dantuma lab..
About our research:
'Ubiquitin Tug-O-War' by Rabiya S. Tuma. 2006. J. Cell Biol. 173(1): 3.
‘Första signalen som skyddar protein i cellen mot nedbrytning’ by Hanna Meerveld. 2005. BiotechSweden 2005(5): 5. (Swedish)
‘Waste disposal under the spotlight’ by M. Brazil. 2003. Nature Rev. Neurosc. 4:698.
‘Ubikvitin:
Det lilla proteinet som styr livet’ by
G. Strachal. 2001. Medicinsk Vetenskap 2001(4): 2-5. (Swedish)
Key references from the Dantuma lab: