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(PP299) Role of homologous recombination in radiation-induced genome instability, adaptive response and bystander effect in vivo.
Kovalchuk, Olga*,1, Koturbash, Igor 1, Hendricks, Carrie2, Stevenson, Sandie 1, Engelward, Bevin*,2, 1 Department of Biological Sciences, Lethbridge, AB, Canada2 Biological Engineering Division, Cambridge, MA, USA
ABSTRACT- Although homologous recombination helps somatic cells repair and tolerate DNA damage, mitotic recombination between misaligned sequences can lead to loss of genetic information (e.g. translocations, LOH). Given that such genetic changes may promote tumorigenesis, it is critical that we learn more about the factors that modulate cellular susceptibility to recombination. Novel transgenic FYDR (fluorescent yellow direct repeat) mice (Recombomice) allow detection of homologous recombination events in vivo (Hendricks, 2003; Kovalchuk, 2004). We have used these mice to compare the effects of chronic and acute exposure to ionizing radiation on homologous recombination in vivo. Strikingly, we found that the same total dose yields opposite effects depending on the duration of the exposure. A single acute dose of radiation induced recombination frequency in FYDR mice. In contrast, the dose administered under chronic exposure conditions suppressed recombination to levels that were significantly below those of unexposed animals. In addition, tissue from chronically irradiated animals showed reduced levels of global methylation and elevated levels of key proteins involved in base excision repair and non-homologous end-joining (specifically, Ape1, Pol and Ku70). Chronic exposure to ionizing radiation also caused the rate of recombination to fall significantly below that of unexposed control animals. Our data clearly indicate that acute and chronic exposure conditions can result in opposite effects, and draw attention to the limits of what can be ascertained from studies of single acute exposures. These results suggest that protective or adaptive responses induced by chronic irradiation may have beneficial effects by suppressing the levels of deleterious sequence rearrangements. Recently we have used Recombomice to study molecular mechanisms of radiation-induced bystander effect in vivo. We have investigated the involvement of DNA damage-induced somatic homologous recombination in bystander effect. Changes in homologous recombination were paralleled by profound epigenetic alterations in bystander tissue. The roles of genetic (recombination) and epigenetic (DNA and histone methylation) changes in radiation-induced genome instability, adaptive response and bystander effect will be discussed.
Key words: homologous recombination, genome instability, adaptive response, bystander effect
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