Self-non-self discrimination is fundamental to life, thereby even microbes can apply DNA modifications to recognize non-self DNA. However, mammalian cytosolic DNA sensors indiscriminately bind DNA, necessitating specific mechanism(s) for self-non-self discrimination. Here, we show that mammalian RNA N6-methyladenosine (m6A) and incoming DNA N6-methyldeoxyadenosine (6mdA) cooperatively elevate the condensation potential of DNA to activate immunosurveillance. RNA m6A modification was found to enhance the activation of cyclic guanosine monophosphate-AMP synthase (cGAS) via increasing DNA phase separation. And 6mdA further increased the phase separation potential of DNA. Consistently, host RNA m6A and incoming DNA 6mdA modifications cooperatively elevated the incoming DNA condensation and cGAS activation. Moreover, we developed a prodrug, QKY-613. QKY-613 promoted a discriminative incorporation of 6mdA into viral DNAs to elevate host immune surveillance, and decreased mortality in virus-infected aged mice. Our results link nucleic acid modification diversity with immune surveillance via phase separation, which might be targeted for therapeutic intervention.

中文翻译：

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宿主 RNA N6-甲基腺苷和传入的 DNA N6-甲基脱氧腺苷修饰协同提高 DNA 的浓缩电位以激活免疫监视


自我非自我辨别是生命的基础，因此即使是微生物也可以应用 DNA 修饰来识别非自我 DNA。然而，哺乳动物胞质 DNA 传感器不分青红皂白地结合 DNA，因此需要特定的机制来实现自我非自我区分。在这里，我们表明哺乳动物 RNA N6-甲基腺苷 （m6A） 和输入的 DNA N6-甲基脱氧腺苷 （6mdA） 协同提高 DNA 的浓缩电位以激活免疫监视。发现 RNA m6A 修饰通过增加 DNA 相分离来增强环磷酸鸟苷-AMP 合酶 （cGAS） 的激活。6mdA 进一步提高了 DNA 的相分离电位。一致地，宿主 RNA m6A 和传入的 DNA 6mdA 修饰协同提高了传入的 DNA 缩合和 cGAS 激活。此外，我们开发了一种前药 QKY-613。QKY-613 促进 6mdA 区分性掺入病毒 DNA 中，以提高宿主免疫监视，并降低病毒感染老年小鼠的死亡率。我们的结果通过相分离将核酸修饰多样性与免疫监测联系起来，这可能是治疗干预的目标。