Abstract
Genomes are mostly protected from constant DNA-damaging threats, either internal or external, which ultimately sustain the organism. Herein, we report that AIMP3, a previously demonstrated tumour suppressor, plays an essential role in maintaining genome integrity in adult mice. Upon induction of the temporal systemic deletion of AIMP3 by tamoxifen in adult mice, the animals developed an acute radiation syndrome-like phenotype, typified by scleroderma, hypotrophy of haematopoietic cells and organs, and intestinal failure. Induction of γH2AX, an early marker of DNA double-strand breaks, was observed in the spleen, intestine, and the highly replicating embryonic cortex. In addition, sub-lethal irradiation of AIMP3 mKO mice dramatically affected organ damage and survival. Using isolated MEFs from conditional KO mice or AIMP3 knockdown cells, we confirmed the presence of spontaneously occurring DNA double-strand breaks by COMET assay and γH2AX induction. Furthermore, γH2AX removal was delayed, and homologous DNA repair activity was significantly reduced. Reduction of RPA foci formation and subsequent Rad51 foci formation probably underlie the significant reduction in homologous recombination activity in the absence of AIMP3. Together, our data demonstrate that AIMP3 plays a role in genome stability through the DNA repair process.
Highlights
Acute radiation syndrome (ARS) is caused by excessive exposure to a high-level radiation source
Correct targeting was confirmed by Southern blot and PCR analysis (Fig. S1)
Our results suggest that AIMP3 plays a critical role in Homologous recombination (HR) repair via the recruitment of RPA and Rad[51]
Summary
Acute radiation syndrome (ARS) is caused by excessive exposure to a high-level radiation source. Mice provide strong evidence of the replicative stress-mediated DNA damage response in vivo[15,16]. Complex networks of DNA damage signalling and repair in replicating cells are not yet clearly understood. In addition to increasing the efficiency of Met-tRNA charging[19], a role for AIMP3 in the activation of the DNA damage response pathway and the suppression of oncogene-mediated transformation has been previously described[20,21]. Our results illustrate that the consequences of AIMP3 deletion include phenotypic recapitulation of ARS, which affects highly dividing tissues, including haematopoietic organs and intestines. Spontaneous DNA strand breakage and reduction of DNA repair activity indicate that AIMP3 contributes to the resolution of DNA damage. The loss of AIMP3 accelerates the response to ARS in vivo, emphasizing its protective role against acute radiation toxicity
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