Modulation of LINE-1 and Alu/SVA Retrotransposition by Aicardi-Goutières Syndrome-Related SAMHD1

Cell Rep. 2013 Sep 26;4(6):1108-15. doi: 10.1016/j.celrep.2013.08.019. Epub 2013 Sep 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements
  • Autoimmune Diseases of the Nervous System / genetics*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Long Interspersed Nucleotide Elements*
  • Monomeric GTP-Binding Proteins / genetics*
  • Nervous System Malformations / genetics*
  • Open Reading Frames
  • Ribonucleoproteins / genetics
  • SAM Domain and HD Domain-Containing Protein 1
  • Sequence Alignment
  • Transfection

Substances

  • Ribonucleoproteins
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Monomeric GTP-Binding Proteins

Supplementary concepts

  • Aicardi-Goutieres syndrome