Long interspersed element-1 (L1) retrotransposons compose ∼20% of the mammalian 
genome, and ongoing L1 retrotransposition events can impact genetic diversity by 
various mechanisms. Previous studies have demonstrated that endogenous L1 
retrotransposition can occur in the germ line and during early embryonic 
development. In addition, recent data indicate that engineered human L1s can 
undergo somatic retrotransposition in human neural progenitor cells and that an 
increase in human-specific L1 DNA content can be detected in the brains of 
normal controls, as well as in Rett syndrome patients. Here, we demonstrate an 
increase in the retrotransposition efficiency of engineered human L1s in cells 
that lack or contain severely reduced levels of ataxia telangiectasia mutated, a 
serine/threonine kinase involved in DNA damage signaling and neurodegenerative 
disease. We demonstrate that the increase in L1 retrotransposition in ataxia 
telangiectasia mutated-deficient cells most likely occurs by conventional 
target-site primed reverse transcription and generate either longer, or perhaps 
more, L1 retrotransposition events per cell. Finally, we provide evidence 
suggesting an increase in human-specific L1 DNA copy number in postmortem brain 
tissue derived from ataxia telangiectasia patients compared with healthy 
controls. Together, these data suggest that cellular proteins involved in the 
DNA damage response may modulate L1 retrotransposition.