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Chair(s): Paretzke, Herwig
(SY056) Early genomic and cellular responses to ionizing radiation.
Mullenders, Leon1, 1 Leiden University Medical Center, Leiden, The Netherlands
ABSTRACT- To make rational judgements in radiation protection, it is necessary to extrapolate from data obtained at relatively high doses to the effects of low doses and low dose-rates, and to have an appreciation of variation in response to ionizing radiation (IR) among the human population. Therefore, a detailed knowledge of the basic mechanisms by which radiation induces cancer and genetic disorders is essential for informed judgements to be made in radiation protection. The two major systems that repair IR induced double- strand breaks in DNA, are homologous recombination (HR) and non-homologous end joining (NHEJ). In addition, activation of cell cycle checkpoints in response to IR damage is equally important as well. In order to fully understand the DNA damage response and to improve quantitative risk modeling, one needs to know the major genetic factors that affect radiation-induced cancer risks. This goal requires the identification of new genes (it is clear that many more genes contribute to radiosensitivity than currently known) and further basic studies on their function. To further expand our knowledge and to identify novel genes, RNA interference (RNAi) was used to systematically screen the genome of the nematode Caenorhabditis elegans for genes, that when inactivated lead to increased radiation sensitivity. In collaboration with the group of Prof. R. Plasterk (Hubrecht Laboratory, Utrecht) we recently completed a screen using a bacterial library that consists of clones producing double-stranded RNA (dsRNA) for nearly 90% of the predicted genes of C. elegans. Among a set of 45 genes that were identified in this way are well known factors, as RAD51 and ATM, but the majority of the genes have not been implicated before in radiation protection. As most of the 45 genes identified have homologs in higher eukaryotes, this screen in C. elegans offers the possibility to study new factors in mammals required for resistance to X-rays and to assess the effects on DNA-damage sensitivity and genetic stability.
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