Induction of mobile genetic elements following exposure to DNA -damaging agents

SINE and LINE elements together comprise over one-third of the human genome. Despite their prevalence, they are relatively replication quiescent. Little is understood about the mechanisms that activate and regulate their transcription and subsequent retrotransposition. We have shown here that DNA-damaging agents are potent inducers of SINE transcription. This increase in transcription is specifically observed following DNA damage, as several cytotoxic agents that act through non-genotoxic means do not activate SINE transcription. Our data comparing the effects of merbarone and etoposide indicate a strong link between DNA cleavage and the SINE transcriptional response.;We have shown that DNA-damaging agents not only increase SINE transcription, but SINE retrotransposition as well. Treatment with a potent DNA-damaging agent induced the retrotransposition of an exogenously added human Alu element in murine cells. This retrotransposition was most likely dependent on endogenous murine LINE elements, as the insertion site characteristics contain hallmarks of LINE-facilitated retrotransposition. Additionally, these data indicated that murine LINE elements could aid the retrotransposition of human SINE elements. Therefore, the requisite machinery needed to support SINE retrotransposition is conserved in murine and human systems.;Finally, we showed that p53 represses SINE transcription and does not contribute to the induction of SINE elements by DNA-damaging agents. Activation of p53 is a common downstream event triggered by all of the classes of DNA-damaging agents analyzed here. Data from cells expressing a dominant-negative p53, as well as mouse primary fibroblasts containing homozygous p53 deletions, showed that the SINE transcriptional response following treatment with DNA-damaging agents is exacerbated in cells lacking functional p53. Therefore, the increase in SINE transcription observed following DNA damage likely occurs through a p53-independent mechanism.