2. Academic Validation
  3. Host RNA N6-methyladenosine and incoming DNA N6-methyldeoxyadenosine modifications cooperatively elevate the condensation potential of DNA to activate immune surveillance

Host RNA N6-methyladenosine and incoming DNA N6-methyldeoxyadenosine modifications cooperatively elevate the condensation potential of DNA to activate immune surveillance

  • Mol Ther. 2024 Oct 28:S1525-0016(24)00687-7. doi: 10.1016/j.ymthe.2024.10.027.
Na Wang 1,  Qiaoling Liu 1,  Bo Wang 2,  Zhuo Yang 3,  Siru Li 1,  Ran Li 1,  Xinyuan Liang 1,  Jiayu Fan 1,  Hui Wang 1,  Zhen Sun 1,  Ling Dong 1,  Yueru Hou 1,  Shengnan Wang 1,  Chengli Song 1,  Yang Wang 1,  Chunshan Quan 4,  Qingkai Yang 5,  Lina Wang 6
Affiliations

Affiliations

  • 1 Institute of Cancer Stem Cell, DaLian Medical University, Dalian 116044, China.
  • 2 Department of General Surgery, The Second Affiliated Hospital of DaLian Medical University, Dalian, China.
  • 3 Department of Gynecology, Cancer Hospital of DaLian University of Technology, Liaoning Cancer Hospital and Institute, Shenyang 110042, China.
  • 4 Department of Bioengineering, College of Life Science, Dalian Minzu University, Dalian 116600, China.
  • 5 Institute of Cancer Stem Cell, DaLian Medical University, Dalian 116044, China. Electronic address: yangqingkai@dmu.edu.cn.
  • 6 Institute of Cancer Stem Cell, DaLian Medical University, Dalian 116044, China. Electronic address: li-nawang@dmu.edu.cn.
PMID: 39473181 DOI: 10.1016/j.ymthe.2024.10.027
Abstract

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.

Keywords

DNA sensor; N(6)-methyladenosine; N(6)-methyldeoxyadenosine; cyclic GMP-AMP synthase; immune surveillance; phase separation.

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