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

• Published in: PLoS genetics 2017-10, Vol.13 (10), p.e1007051
• Main Authors: Ward, Jacqueline R, Vasu, Kommireddy, Deutschman, Emily, Halawani, Dalia, Larson, Peter A, Zhang, Dongmei, Willard, Belinda, Fox, Paul L, Moran, John V, Longworth, Michelle S
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - genetics; Biology and life sciences; Cancer; Cell Cycle Proteins - genetics; Cellular proteins; Condensin; Cooperation; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - genetics; Epithelial cells; Epithelial Cells - metabolism; Gait; Gene expression; Genetic aspects; Genome, Human; Genomes; Glyceraldehyde; Glyceraldehyde 3-phosphate; Glyceraldehyde-3-phosphate dehydrogenase; Health aspects; Humans; Immunoprecipitation; Inflammation; Initiation complex; Interferon; Interferon-gamma - genetics; Interferon-Stimulated Gene Factor 3 - genetics; Kinases; Long Interspersed Nucleotide Elements - genetics; Medical research; Medicine; Medicine and Health Sciences; Multiprotein Complexes - genetics; Mutation; Myeloid cells; Nuclear Proteins - genetics; Proline-tRNA ligase; Protein Binding; Protein Synthesis Inhibitors; Proteomics; Research and Analysis Methods; Retroelements - genetics; Retrotransposition; Retrotransposons; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA-protein interactions; Somatic cells; Transcription; Translation; Translation initiation; tRNA; γ-Interferon
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1007051

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.