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

Yang Zhao, Ena Oreskovic, Quanwei Zhang, Quan Lu, Abbey Gilman, Yifei S. Lin, Junyue He, Zhizhong Zheng, J. Yuyang Lu, Jina Lee, Zhonghe Ke, Julia Ablaeva, Matthew J. Sweet, Steve Horvath, Zhengdong Zhang, Eviatar Nevo, Andrei Seluanov, Vera Gorbunova

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1219-1230
Number of pages12
JournalNature Immunology
Volume22
Issue number10
DOIs
StatePublished - Oct 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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