Nature Immunology, Zhao Yang and others found that blind mole rats use "junk DNA" to fight cancer

Responsible editor | Xi's selfish genetic elements were once thought to be mere parasites of the genome
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The blind mole rat (Spalax ehrenbergi) living in the Middle East and Eastern Europe is a small rodent that lives underground.
The most notable feature is that it is extremely resistant to spontaneous or induced cancer and has a maximum life span of more than 21 years
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The mechanism of its anti-cancer and longevity has been unclear
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Early studies have shown that when blind mole fibroblasts proliferate excessively, a synchronous cell death called CCD (concerted cell death) occurs.
Research suggests that this phenomenon is related to interferon, but the mechanism is not Clear
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On September 23, 2021, the team of Vera Gorbunova and Andrei Seluanov of the University of Rochester in the United States published a research paper entitled Transposon-triggered innate immune response confers cancer resistance to the blind mole rat in Nature Immunology, which first revealed the anti-cancer effect of blind mole rat Mechanism
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The author first compared the transcriptome of blind mole cells during CCD and normal proliferation, and found that type I interferon pathway genes were generally up-regulated, including interferon (IFN)
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Since CCD occurs in a sterile cell culture environment, the author speculates that the expression of interferon is a sterile inflammatory response triggered by the expression of an endogenous component, and the most likely one is the overexpression of the transposon
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In order to prevent the transposon from jumping, under normal circumstances, the transposon is inhibited by epigenetic modifications such as DNA methylation
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"But when animals age," said Gorbunova, the corresponding author of the article, "This epigenetic mechanism malfunctions, awakening the transposon and causing damage
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When the author compared the blind mole cells with normal proliferation and CCD, they found that the RNA level of a large number of retrotransposons increased significantly with the occurrence of CCD
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Correspondingly, the expression level of DNMT1, an enzyme responsible for maintaining DNA methylation, in blind mole cells and tissues is also significantly lower than that of humans or mice
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Further research found that due to the low expression of DNMT1, methylation in the rapidly proliferating blind mole cells could not keep up with the cell proliferation rate, resulting in demethylation and increased expression of a large number of retrotransposons in the genome, and the latter formed in the cytoplasm.
The RNA-DNA hybrid activates the cGAS-STING-IFN pathway to kill over-proliferating cells
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In nude mouse xenotransplantation experiments, blind mole mouse cells could not be transformed into cancer cells; but when knocking down cGAS or treating mice with anti-HIV reverse transcriptase inhibitors, blind mole mouse cells could form tumors
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The author further explores whether this mechanism is applicable to a wider range of situations
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The study found that by knocking down DNMT1 or overexpressing the two main retrotransposons LINE1 and SINEs, chemically induced cancers in human cancer cell lines and mice were inhibited, suggesting that retrotransposons can be more common The range functions as a tumor suppressor (Figure 1)
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Figure 1 The anti-cancer mechanism of the blind mole rat and its general applicability in humans and mice "These results indicate that although humans have not evolved the same anti-cancer mechanism as the blind mole rat, it is possible to modify related pathways "Helping humans treat cancer" Gorbunova said, "These findings suggest that retrotransposon activation is a double-edged sword
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Nature Reviews Immunology published an online article entitled The mole rat's secret to cancer resistance on September 28, and commented on the highlights of this research
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The commentary stated that the study has discovered a new mechanism for blinded mole rats to fight cancer, suggesting that retrotransposons are not only traditionally thought of as selfish genomic parasites, but can also act as tumor suppressors
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The first author of the study is Zhao Yang, a postdoctoral researcher at the University of Rochester
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University of California, Los Angeles, Steve Horvath (inventor of the methylation clock), and Eviatar Nevo of the University of Haifa in Israel also participated in the research
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