Abstract
High-linear energy transfer ionizing radiation, derived from high charge (Z) and energy (E) (HZE) particles, induces clustered/complex DNA double-strand breaks (DSBs) that include small DNA fragments, which are not repaired by the non-homologous end-joining (NHEJ) pathway. The homologous recombination (HR) DNA repair pathway plays a major role in repairing DSBs induced by HZE particles. The Mre11 complex (Mre11/Rad50/NBS1)-mediated resection of DSB ends is a required step in preparing for DSB repair via the HR DNA repair pathway. Here we found that expression of Bcl2 results in decreased HR activity and retards the repair of DSBs induced by HZE particles (i.e. 56iron and 28silicon) by inhibiting Mre11 complex activity. Exposure of cells to 56iron or 28silicon promotes Bcl2 to interact with Mre11 via the BH1 and BH4 domains. Purified Bcl2 protein directly suppresses Mre11 complex-mediated DNA resection in vitro. Expression of Bcl2 reduces the ability of Mre11 to bind DNA following exposure of cells to HZE particles. Our findings suggest that, after cellular exposure to HZE particles, Bcl2 may inhibit Mre11 complex-mediated DNA resection leading to suppression of the HR-mediated DSB repair in surviving cells, which may potentially contribute to tumor development.
Highlights
Terrestrial radiation is largely characterized by low-linear energy transfer radiation (i.e. X, - or ␥ -rays) while space radiation is characterized by high-linear energy transfer ionizing radiation [1]
High-LET IR derived from HZE 56Fe or 28Si particles induced ␥ H2AX and 53BP1 foci along the ion track while low-linear energy transfer (low-LET) IR induced double-strand breaks (DSBs) foci with sparse ionization, and DNA breaks were scattered more evenly throughout the nucleus (Figure 1)
Both high- and low-LET IR produce similar DSB numbers, the closely packed DSBs caused by high-LET IR are more likely to result in the generation of small double stranded DNA fragments compared to low-LET IR [38,39]
Summary
Terrestrial radiation is largely characterized by low-linear energy transfer (low-LET) radiation (i.e. X-, - or ␥ -rays) while space radiation is characterized by high-linear energy transfer ionizing radiation (high-LET IR) [1]. Clustered DSBs may be converted into replicative DSBs in S phase These replicative breaks as well as persistent frank DSBs left unrepaired by nonhomologous end-joining (NHEJ) may be repaired by homologous recombination (HR) [6]. It has recently been reported that high-LET IR derived from 56iron (56Fe) ion can inhibit the Ku-dependent main NHEJ pathway by the generation of small fragments of DNA DSBs (
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