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

doi:10.1038/s41590-021-01027-8

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

Department of Evolutionary and Environmental Biology

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1219-1230
Number of pages	12
Journal	Nature Immunology
Volume	22
Issue number	10
DOIs	https://doi.org/10.1038/s41590-021-01027-8
State	Published - Oct 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41590-021-01027-8

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Zhao, Y., Oreskovic, E., Zhang, Q., Lu, Q., Gilman, A., Lin, Y. S., He, J., Zheng, Z., Lu, J. Y., Lee, J., Ke, Z., Ablaeva, J., Sweet, M. J., Horvath, S., Zhang, Z., Nevo, E., Seluanov, A., & Gorbunova, V. (2021). Transposon-triggered innate immune response confers cancer resistance to the blind mole rat. Nature Immunology, 22(10), 1219-1230. https://doi.org/10.1038/s41590-021-01027-8

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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.",

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

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doi = "10.1038/s41590-021-01027-8",

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Zhao, Y, Oreskovic, E, Zhang, Q, Lu, Q, Gilman, A, Lin, YS, He, J, Zheng, Z, Lu, JY, Lee, J, Ke, Z, Ablaeva, J, Sweet, MJ, Horvath, S, Zhang, Z, Nevo, E, Seluanov, A & Gorbunova, V 2021, 'Transposon-triggered innate immune response confers cancer resistance to the blind mole rat', Nature Immunology, vol. 22, no. 10, pp. 1219-1230. https://doi.org/10.1038/s41590-021-01027-8

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T1 - Transposon-triggered innate immune response confers cancer resistance to the blind mole rat

AU - Zhao, Yang

AU - Oreskovic, Ena

AU - Zhang, Quanwei

AU - Lu, Quan

AU - Gilman, Abbey

AU - Lin, Yifei S.

AU - He, Junyue

AU - Zheng, Zhizhong

AU - Lu, J. Yuyang

AU - Lee, Jina

AU - Ke, Zhonghe

AU - Ablaeva, Julia

AU - Sweet, Matthew J.

AU - Horvath, Steve

AU - Zhang, Zhengdong

AU - Nevo, Eviatar

AU - Seluanov, Andrei

AU - Gorbunova, Vera

PY - 2021/10

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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