Group name: Department of Pathology
Other staff
members: Wim Vermeulen,
Jan Hoeijmakers, Roland Kanaar
Location: Josephine Nefkens Institute, Erasmus University Rotterdam
Web page:
E-Mail: houtsmuller@path.fgg.eur.nl
Phone: +31 10 4088 456
Relevant research interests:
At present, enormous amounts of data are being generated by several types of large-scale genomics and proteomics research. Computer-aided analysis methodology (‘bioinformatics’) for the interpretation of this data is currently an intensively explored area, and co-ordinated efforts are being made in many institutes to install this methodology in bioinformatics core facilities. However, to fully understand, predict (and interfere with) the complexity of cellular (dys)function, further in-depth study of the specific proteins and pathways elucidated with the above approaches is required.
The rapid development of green fluorescent protein
(GFP) technology and continuous innovation of digital imaging equipment and
quantitative fluorescence assays have revolutionised the study of proteins and
protein-protein interactions in living cells. At present, several research
groups within the Erasmus MC (and co-operating groups in other institutes) have
embarked upon this novel, challenging area of research to explore vital
cellular processes including gene transcription regulation, DNA repair and
telomere function in the living cell. The research
aims at unravelling the reaction mechanisms of these processes and to dissect
the nature and order of consecutive reaction steps. In addition, the developed
technology offers new opportunities to study (therapeutic) interference with
protein function and interactions, opening the way to develop and apply novel
(high throughput) screening methodology to find new targets for cancer therapy.
Briefly, in this type of research
the dynamic properties of and interactions between
fluorescently labeled proteins are determined in vivo using time-lapse microscopic imaging and state-of-the-art
quantitative fluorescence assays. For translation of
the massive amount of complex data (obtained by these and other ‘-omics’ approaches) into physical properties of
individual protein activities and, most important, for understanding the
complexity of multiple protein-protein interactions in different cellular
processes (‘molecular networks’), and interaction between these processes,
computer modelling is indispensable.
Current system biology activities:
The primary goal of our current research in ‘systems
biology’ is to create a computer modelling environment that serves as an
interface between experiment-based computer modelling
and computer-model-based experiments. This approach is expected to advance our knowledge of
1), the in vivo behaviour and
interactions of cellular proteins in the context of the processes they are
involved in, 2) the interaction/cross-talk between these processes, 3) the molecular changes (eg. by mutations) that affect the proper regulation of these
processes, and/or the interaction between these processes, leading to malignant
growth, and 4) the action mechanisms of methods to interfere with these
(deviant) processes.
Relevant collaborations:
Representative publications (possibly
links to pdf files):
1.
Houtsmuller A.B., Rademakers S., Nigg A.L., Hoogstraten D., Hoeijmakers
J.H.J. and Vermeulen W. Action of DNA repair endonuclease ERCC1/XPF in living
cells. Science 284, 958-961 (1999).
2.
Essers J., Houtsmuller A.B., van Veelen L.., Paulusma C., Nigg A.L.,
Pastink A., Vermeulen W., Hoeijmakers J.H.J. and Kanaar R. Nuclear dynamics of
RAD52 group homologous recombination proteins in response to DNA damage. EMBO J.
21, 2030-2037 (2002).
3.
Hoogstraten D., Nigg A.L., Heath H., Mullenders L.H.F., van Driel R.,
Hoeijmakers J.H.J., Vermeulen W. and Houtsmuller A.B. Rapid switching of TFIIH
between RNA polymerase I and II transcription and DNA repair in vivo. Mol Cell 10: 1163-1174 (2002).
4.
Houtsmuller A.B. and Vermeulen W. Macromolecular dynamics in living
cell nuclei revealed by fluorescence redistribution after photobleaching. Histochem Cell Biol 5, 13-21 (2001).