Feedback inhibition of L1 and alu retrotransposition through altered double strand break repair kinetics

We demonstrate that constitutive L1 expression leads to quicker DSB repair and decreases in the retrotransposition potential of L1 and other retrotransposons dependent on L1 expression for their mobility. This cellular adaptation results in reduced sensitivity to L1 induced toxicity. These effects can be induced by constitutive expression of the functional L1 ORF2 alone, but not by the constitutive expression of an L1 open reading frame 2 with mutations to its endonuclease and reverse transcriptase domains. This adaptation correlates with the relative activity of the L1 introduced into the cells.The increased number of DSBs resulting from constitutive expression of L1 results in a more rapid rate of repair. The cellular response to this L1 expression also results in attenuation of retrotransposition and reduced sensitivity of the cells to negative consequences of L1 ORF2 expression. The influence does not appear to be through RNA interference. We believe that the increased rate of DSB repair is the most likely cause of the attenuation of retrotransposition. These alterations act as a fail safe mechanism that allows cells to escape the toxicity associated with the unchecked L1 expression. This gives cells that overexpress L1, such as tumor cells, the ability to survive the high levels of expression. However, the increased rate of break repair may come at the cost of accuracy of repair of the lesion, resulting in increased genomic instability.Mammalian cells often evolve adaptive responses to deal with chronic exposure to various toxic agents, including ethanol and opiates [1-4]. Cells also adapt to chronic exposure to sublethal doses of DNA double strand breaks (DSBs) through the selection of cells with altered DSB repair [1]. Typically, mammalian cells depend on a balance between two broad classes of DSB repair to ensure proper genome maintenance. Homologous repair (HR) is a process largely dependent on homology, whereas non-homologous end joining (NHEJ) is mostly i