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Chair(s): Chen, David; Powell, Simon
(MS007) Extensive and asynchronous H2AX phosphorylation after ionizing irradiation.
Han, Jianxun*,1, Hendzel, Michael1, 2, Turner, Joan1, 2, 1 Department of Oncology, Edmonton, Alberta, Canada2 Division of Experimental Oncology, Edmonton, Alberta, Canada
ABSTRACT- DNA double-strand breaks (DSB) are believed to be the major threat to cellular genome stability after ionizing irradiation (IR). In order to maintain genome stability, eukaryotic cells have evolved two major pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), to efficiently repair DSBs. Although there are many differences between these two pathways, they both take place in the context of chromatin. Therefore, it is not surprising that histone modification and other processes involved in chromatin remodeling have been found to play an important role in DSB repair. Among these processes, the first, and the best, studied is the phosphorylation of H2AX at DSB sites. This phosphorylation occurs immediately after IR and extends to a region that includes as much as 30Mb chromatin to form visible microscopic structures called -H2AX foci. Despite the fact that it has been well established that cellular H2AX phosphorylation level reach peak levels 30min after IR, the kinetics and extent of phosphorylation of individual -H2AX foci are not well understood. Using objective analyzing individual -H2AX foci, we showed that: 1) H2AX phosphorylation also occurs outside of DSB sites after IR; 2) H2AX phosphorylation at different DSB sites is asynchronous after IR, this may reflect the heterogeneous character of free DNA ends after IR; and 3) at the highest phosphorylation level of each individual -H2AX focus, it is possible that all the H2AX molecules within this focus are phosphorylated. Combining these data with information from other studies, we propose that the H2AX phosphorylation is a direct marker of chromatin remodeling after IR rather than a specific indicator of DSB formation.
Key words: double-strand break, -H2AX foci, chromatin remodeling
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