Condensin II and GAIT complexes cooperate to restrict LINE-1 retrotransposition in epithelial cells

PLoS Genet. 2017 Oct 13;13(10):e1007051. doi: 10.1371/journal.pgen.1007051. eCollection 2017 Oct.

Abstract

LINE-1 (L1) retrotransposons can mobilize (retrotranspose) within the human genome, and mutagenic de novo L1 insertions can lead to human diseases, including cancers. As a result, cells are actively engaged in preventing L1 retrotransposition. This work reveals that the human Condensin II complex restricts L1 retrotransposition in both non-transformed and transformed cell lines through inhibition of L1 transcription and translation. Condensin II subunits, CAP-D3 and CAP-H2, interact with members of the Gamma-Interferon Activated Inhibitor of Translation (GAIT) complex including the glutamyl-prolyl-tRNA synthetase (EPRS), the ribosomal protein L13a, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and NS1 associated protein 1 (NSAP1). GAIT has been shown to inhibit translation of mRNAs encoding inflammatory proteins in myeloid cells by preventing the binding of the translation initiation complex, in response to Interferon gamma (IFN-γ). Excitingly, our data show that Condensin II promotes complexation of GAIT subunits. Furthermore, RNA-Immunoprecipitation experiments in epithelial cells demonstrate that Condensin II and GAIT subunits associate with L1 RNA in a co-dependent manner, independent of IFN-γ. These findings suggest that cooperation between the Condensin II and GAIT complexes may facilitate a novel mechanism of L1 repression, thus contributing to the maintenance of genome stability in somatic cells.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Cell Cycle Proteins / genetics*
  • DNA-Binding Proteins / genetics
  • Epithelial Cells / metabolism
  • Genome, Human
  • Humans
  • Interferon-Stimulated Gene Factor 3 / genetics
  • Interferon-gamma / genetics*
  • Long Interspersed Nucleotide Elements / genetics*
  • Multiprotein Complexes / genetics
  • Nuclear Proteins / genetics*
  • Protein Binding
  • Protein Synthesis Inhibitors
  • RNA, Messenger / genetics
  • Retroelements / genetics

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Interferon-Stimulated Gene Factor 3
  • Multiprotein Complexes
  • NCAPD3 protein, human
  • NCAPH protein, human
  • Nuclear Proteins
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Retroelements
  • condensin complexes
  • gamma interferon activation factor
  • Interferon-gamma
  • Adenosine Triphosphatases