Chromosomal aberrations constitute a prominent hallmark of human cancers. Over a broad dose range (down to less than 100mGy),
ionizing radiation is a potent inducer of chromosomal aberrations. Various studies have indicated that proximity of chromosome
territories (CTs) within interphase nuclei has a strong impact on the formation of chromosome exchange aberrations both
spontaneously and after ionizing radiation (Nikiforova et al. 2000, Bickmore and Teaque 2002, Roix et al. 2003, Arsuaga et al. 2004).
Consequently, chromosomal aberrations might differ for various tissues reflecting the tissue specific relative positioning of CTs.
Very recently, novel insights have been gained on CT arrangements in fibroblasts (Bolzer et al, 2005) that contrast to lymphocytes,
in fibroblasts CT arrangements correlate mainly with the size, in human lymphocytes with the gene density.
In the framework of the European Union funded RiscRad project, in collaboration with our partners in Leiden
(Jan Boei, Leon Mullenders) we investigate differences in the induction of chromosomal aberrations in human
fibroblast nuclei when a size correlated distribution of CTs in human cell nuclei is assumed by model calculations.
Our main research foci in the RiscRad project are:
Experimental validation of predictive frequencies of chromosomal aberrations in human fibroblasts. Experimental information
of CT arrangements will be used in numerical modeling studies to simulate aberration formation. Validation of predicted relative
exchange frequencies will be made by in vitro exposure of fibroblasts and subsequent analysis of metaphase chromosomes
using multi-colour FISH (Fluorescence In Situ Hybridization) chromosome painting. Since previous experiments have indicated
that high LET (Linear Energy Transfer) radiation is more powerful to link chromosome interphase positioning to chromosomal
aberrations, we will employ exposure with fission neutrons. A number of chromosomes with a particular positioning or predicted
exchange yield will be selected.
Improvement of basic knowledge of morphology of CTs for better understanding of the formation of chromosomal aberrations
after ionizing radiation. Basic knowledge on the morphology of CTs (i.e. chromatin loop structure) is still very poor and hence,
computer simulations are lacking accurate parameters dealing with CT shape and volume. By accurate volume measurements of
interphase CTs after 3D conserved chromosome painting and by the application of novel lightoptical approaches to study chromatin
folding within the nucleus with unprecedented spatial resolution such as Spectral Precision Distance/Spectral Position Determination
Microscopy (SPDM) using photoconvertable spectral signatures, we will generate data to further optimize computer simulations of
chromosomal interphase architecture and IR induced chromosomal aberrations.
Visualization of numerically modeled human lymphocyte nuclei. Left: 3D visualizations of gene poor CTs #18 (brown)
and #21 (light blue) which are located more in the periphery of the lymphocyte nucleus. Right: 3D visualizations
of the gene rich CTs #19 (blue),#17 (green),#22 (yellow) which are located more in the interior.
Comparison between calculated and experimentally observed Centric and Dicentric aberration yields in dependency of
the dose for Low LET irradiation (aus Kreth et al. 2007)
W. Friedland, H. G. Paretzke, F. Ballerini, A. Ottolenghi, G. Kreth, C. Cremer (2008), First Steps towards systems
radiation biology studies concerned with DNA and chromosome structure within living cells.
Radiat. Environ. Biophys. DOI 10.1007/s00411–007–0152–x (2008)
G. Kreth, C. Cremer (2007), Chromatin Structure and the Formation of Chromosomal Alterations in Chromosomal Alterations:
Methods, Results and Importance in Human Health, Eds. Günter Obe abd Vijayalaxmi, Springer Verlag Heidelberg (2007)
G. Kreth, S.K. Pazhanisamy, M. Hausmann, C. Cremer (2007), Cell type–specific quantitative predictions of
radiation-induced chromosome aberrations: A computer model approach. Radiat. Res. 167: 515–525 (2007)
G. Kreth, C. Cremer (2005), "Biocomputing": strahlenbiologische Risikovorhersage, Ruperto Carola, Forschungsmagazin
der Universität Heidelberg, (2005)
For more publications see publicationlist on top of page.