Transposon-triggered innate immune response confers cancer resistance to the blind mole rat [array]

Blind mole rats (BMRs) are small rodents, characterized by 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). BMR cells and tissues express very low levels of DNA methyltransferase 1 (DNMT1). Upon cell hyperplasia, the BMR genome DNA loses methylation, resulting in activation of RTEs. Up-regulated RTEs form cytoplasmic RNA/DNA hybrids, which activate cGAS-STING pathway to induce cell death. Although this mechanism is enhanced in the BMR, we show that it functions in mice and human. We propose that RTEs were coopted to serve as tumor suppressors that monitor cell proliferation and are activated in premalignant cells to trigger cell death via activation of innate immune response. RTEs activation is a double-edged sword, serving as a tumor suppressor but in late life contributing to aging via induction of sterile inflammation. Using a custom Illumina chip HorvathMammalMethylChip40, we compared methylation of 37K conserved CpG sites between blind mole rat and mouse fibrolasts for both young and overproliferated cells. Five cell lines from each species were used for paired comparison.