RESUMO
Blind mole rats (BMRs) are small rodents, characterized by an exceptionally long lifespan (>21 years) and resistance to both spontaneous and induced tumorigenesis. Here we report that cancer resistance in the BMR is mediated by retrotransposable elements (RTEs). Cells and tissues of BMRs express very low levels of DNA methyltransferase 1. Following cell hyperplasia, the BMR genome DNA loses methylation, resulting in the activation of RTEs. Upregulated RTEs form cytoplasmic RNA-DNA hybrids, which activate the cGAS-STING pathway to induce cell death. Although this mechanism is enhanced in the BMR, we show that it functions in mice and humans. We propose that RTEs were co-opted to serve as tumor suppressors that monitor cell proliferation and are activated in premalignant cells to trigger cell death via activation of the innate immune response. Activation of RTEs is a double-edged sword, serving as a tumor suppressor but contributing to aging in late life via the induction of sterile inflammation.
Assuntos
Elementos de DNA Transponíveis/imunologia , Imunidade Inata/imunologia , Ratos-Toupeira/imunologia , Neoplasias/imunologia , Animais , Carcinogênese/imunologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células Cultivadas , DNA/imunologia , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Ratos , Transdução de Sinais/imunologiaRESUMO
Home information profoundly influences behavioral states in both humans and animals. However, how "home" is represented in the brain and its role in driving diverse related behaviors remain elusive. Here, we demonstrate that home bedding contains sufficient home information to modulate affective behaviors, including aversion responses, defensive aggression, and mating behaviors. These varied responses to home information are mediated by gama-aminobutyric acid (GABA)ergic neurons in the lateral hypothalamus (LHGABA). Inhibiting LHGABA abolishes, while activating mimics, the effects of home bedding on these behaviors across different contexts. Specifically, projections from LHGABA to the ventral tegmental area (VTA) mediate the relaxation of aversive emotion, while projections to the periaqueductal gray (PAG) initiate defensive concerns. Thus, our data suggest that home information in different contexts converges to activate distinct subgroups of the LHGABA, which, in turn, elicit appropriate affective behaviors in relieving aversion, fighting intruders, or enhancing mating through involving distinct downstream projections.