Abstract
Ionizing radiation (IR)-induced DNA double-strand breaks trigger an extensive cellular signaling response that involves the coordination of hundreds of proteins to regulate DNA repair, cell cycle arrest and apoptotic pathways. The cellular outcome often depends on the level of DNA damage as well as the particular cell type. Proliferating zebrafish embryonic neurons are highly sensitive to IR-induced apoptosis, and both p53 and its transcriptional target puma are essential mediators of the response. The BH3-only protein Puma has previously been reported to activate mitochondrial apoptosis through direct interaction with the pro-apoptotic Bcl-2 family proteins Bax and Bak, thus constituting the role of an “activator” BH3-only protein. This distinguishes it from BH3-only proteins like Bad that are thought to indirectly promote apoptosis through binding to anti-apoptotic Bcl-2 family members, thereby preventing the sequestration of activator BH3-only proteins and allowing them to directly interact with and activate Bax and Bak. We have shown previously that overexpression of the BH3-only protein Bad in zebrafish embryos supports normal embryonic development but greatly sensitizes developing neurons to IR-induced apoptosis. While Bad has previously been shown to play only a minor role in promoting IR-induced apoptosis of T cells in mice, we demonstrate that Bad is essential for robust IR-induced apoptosis in zebrafish embryonic neural tissue. Moreover, we found that both p53 and Puma are required for Bad-mediated radiosensitization in vivo. Our findings show the existence of a hierarchical interdependence between Bad and Puma whereby Bad functions as an essential sensitizer and Puma as an essential activator of IR-induced mitochondrial apoptosis specifically in embryonic neural tissue.
Highlights
Cellular exposure to ionizing radiation (IR) causes multiple forms of DNA damage, including single- and double-stranded breaks (DSB), within the sugar-phosphate backbone of DNA
Studies using peptides derived from individual BH3 domains suggested that both PUMA and BAD act indirectly to activate BAX and BAK, through binding to and inactivating antiapoptotic Bcl-2 family proteins
It was shown that PUMA is required for BAD to induce apoptosis when overexpressed in mouse embryonic fibroblasts
Summary
Cellular exposure to ionizing radiation (IR) causes multiple forms of DNA damage, including single- and double-stranded breaks (DSB), within the sugar-phosphate backbone of DNA. When two single-stranded breaks occur in close proximity to each other, the resultant DSB represents a threat to genome stability. The presence of DNA DSBs elicits an extensive cellular response that coordinates decisions to undergo cell cycle arrest, DNA repair and apoptosis. In response to IR exposure, certain cell types appear to be programmed to favor cell cycle arrest and DNA repair over apoptosis (e.g. fibroblasts) and vice versa (e.g. T cells) [1]. The sensitivity of tissues to IR-induced apoptosis can change over the course of development. Proliferating embryonic neurons are highly sensitive to IR-induced apoptosis whereas differentiated, mature neurons are highly resistant [1,2]
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