title: Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production.
abstract: Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4(FANCP) deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition. Importantly, similar results were obtained with the FANCD2 upstream activator of SLX4. Furthermore, treatment of FA cells with the Tenofovir reverse transcriptase inhibitor (RTi), that prevents endogenous retrotransposition, decreased both accumulation of cytoplasmic DNA and pro-inflammatory signaling. Collectively, our data suggest a contribution of endogenous RT activities to the generation of immunogenic cytoplasmic nucleic acids responsible for inflammation in FA. The additional observation that RTi decreased pro-inflammatory cytokine production induced by DNA replication stress-inducing drugs further demonstrates the contribution of endogenous RTs to sustaining chronic inflammation. Altogether, our data open perspectives in the prevention of adverse effects of chronic inflammation in tumorigenesis.
authors.affiliation: Institute of Human Genetics, CNRS UPR1142, Molecular Basis of Cancer-Related Inflammation Laboratory, University of Montpellier, Montpellier, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Brégnard
authors.affiliation: Institute of Human Genetics, CNRS UPR1142, Molecular Basis of Cancer-Related Inflammation Laboratory, University of Montpellier, Montpellier, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Guerra
authors.affiliation: Institute of Human Genetics, CNRS UPR1142, Molecular Basis of Cancer-Related Inflammation Laboratory, University of Montpellier, Montpellier, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Déjardin
authors.affiliation: Institute of Human Genetics, CNRS UPR1142, Molecular Basis of Cancer-Related Inflammation Laboratory, University of Montpellier, Montpellier, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Passalacqua
authors.affiliation: Institute of Human Genetics, CNRS UPR1142, Molecular Virology Laboratory, University of Montpellier, Montpellier, France. Electronic address: monsef.benkirane@igh.cnrs.fr.
authors.forename: Monsef
authors.initials: M
authors.lastname: Benkirane
authors.affiliation: Institute of Human Genetics, CNRS UPR1142, Molecular Basis of Cancer-Related Inflammation Laboratory, University of Montpellier, Montpellier, France. Electronic address: nadine.laguette@igh.cnrs.fr.
authors.forename: Nadine
authors.initials: N
authors.lastname: Laguette
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D003593:Cytoplasm; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D005199:Fanconi Anemia / Q000150:complications* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007372:Interferons / Q000096:biosynthesis; D020084:Long Interspersed Nucleotide Elements; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism*; D045522:Recombinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics
chemical_list: D016207:Cytokines; D004277:DNA, Single-Stranded; D018836:Inflammation Mediators; D045522:Recombinases; D018626:Retroelements; D007372:Interferons; C542319:SLX4 protein, human
keywords: Cytoplasmic DNA; DNA damage; Fanconi Anemia; Inflammation; Innate immune sensing; Interferon; SLX4 complex; cGAS-STING; endogenous retroelement