ID: 110: Type 1 interferons as guardians of genome integrity and mediators of aging

Abstract

Type 1 IFNs (IFN1) are potent anti-viral cytokines. Here we report that IFN1 are expressed in cells that harbor activated Long Interspersed Element-1 (LINE-1) mobile genetic retrotransposon elements. IFN1 inhibits activities and propagation of LINE-1 in vitro and in vivo. While endonuclease activity of LINE-1 was required for IFN1 production, we also found that double strand DNA breaks (DSB) in general represent a potent IFN1-inducing signal that activates IFN1 signaling. Cells and tissues experiencing persistent DSB are characterized by increased IFN1 signaling. Experiments in mouse and human cells that harbor numerous DSB demonstrated that DSB-induced IFN1 signaling play a paramount role in DSB-induced cell senescence. Mice lacking the Terc telomerase component (harboring shortened telomeres and persistent DSB) exhibited activated IFN1 signaling concurrent with profound failure of their somatic and germinal stem cells that manifested in progeric phenotypes including impaired fertility and fecundity, atrophy in testes, skin, hematopoietic and intestinal compartments, and shortened life span. All these phenotypes could be substantially alleviated by concurrent ablation of Ifnar1 suggesting a role for IFN1 in accelerated aging. Furthermore, these data indicate that IFN1 acts as a guardian of genome integrity at many levels including single cell (by preventing the spread of retrotransposons), individual multi-cellular organism (by senescence-mediated prevention of proliferation of damaged cells) and biological population (by suppressing the offspring from species harboring altered genome). These non-canonical novel functions of IFN1 are of potential medical significance for treating patients with progerias and protecting individuals exposed to harmful agents that cause massive DNA damage.