title: Cre-dependent DNA recombination activates a STING-dependent innate immune response.
abstract: Gene-recombinase technologies, such as Cre/loxP-mediated DNA recombination, are important tools in the study of gene function, but have potential side effects due to damaging activity on DNA. Here we show that DNA recombination by Cre instigates a robust antiviral response in mammalian cells, independent of legitimate loxP recombination. This is due to the recruitment of the cytosolic DNA sensor STING, concurrent with Cre-dependent DNA damage and the accumulation of cytoplasmic DNA. Importantly, we establish a direct interplay between this antiviral response and cell-cell interactions, indicating that low cell densities in vitro could be useful to help mitigate these effects of Cre. Taking into account the wide range of interferon stimulated genes that may be induced by the STING pathway, these results have broad implications in fields such as immunology, cancer biology, metabolism and stem cell research. Further, this study sets a precedent in the field of gene-engineering, possibly applicable to other enzymatic-based genome editing technologies.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Pépin
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ferrand
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, 53127 Bonn, Germany.
authors.forename: Klara
authors.initials: K
authors.lastname: Höning
authors.affiliation: Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: W Samantha N
authors.initials: WS
authors.lastname: Jayasekara
authors.affiliation: Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Cain
authors.affiliation: Integrated DNA Technologies Inc., Coralville, IA 52241, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Behlke
authors.affiliation: Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gough
authors.affiliation: Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: G Williams
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, 53127 Bonn, Germany Gene Centre and Department of Biochemistry, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia michael.gantier@hudson.org.au.
authors.forename: Michael P
authors.identifier: 0000-0003-3740-698X
authors.initials: MP
authors.lastname: Gantier
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D007113:Immunity, Innate; D019426:Integrases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D000099197:STING Protein
chemical_list: D019426:Integrases; D008565:Membrane Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C045073:Cre recombinase