Long interspersed elements 1 (LINE-1) occupy at least 17% of the human genome 
and are its only active autonomous retrotransposons. However, the host factors 
that regulate LINE-1 retrotransposition are not fully understood. Here, we 
demonstrate that the Aicardi-Goutières syndrome gene product SAMHD1, recently 
revealed to be an inhibitor of HIV/simian immunodeficiency virus (SIV) 
infectivity and neutralized by the viral Vpx protein, is also a potent regulator 
of LINE-1 and LINE-1-mediated Alu/SVA retrotransposition. We also found that 
mutant SAMHD1s of Aicardi-Goutières syndrome patients are defective in LINE-1 
inhibition. Several domains of SAMHD1 are critical for LINE-1 regulation. SAMHD1 
inhibits LINE-1 retrotransposition in dividing cells. An enzymatic active site 
mutant SAMHD1 maintained substantial anti-LINE-1 activity. SAMHD1 inhibits 
ORF2p-mediated LINE-1 reverse transcription in isolated LINE-1 
ribonucleoproteins by reducing ORF2p level. Thus, SAMHD1 may be a cellular 
regulator of LINE-1 activity that is conserved in mammals.