Nature structural & molecular biology · 2026
Redox-driven ADAR1 activation promotes Okazaki fragment maturation and DNA replication integrity.
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Chen Bin, Sun Guangchao, Kloeber Jake A, Xiao Huaping, Ouyang Yaobin, Zhao Fei, Li Ya, Xu Shilin, Dragojevic Sonja, Wu Zheming, Zhu Shouhai, Han Yiqun, Yin Ping, Tu Xinyi, Qin Hongran, Zhou Xiang, Luo Kuntian, Peterson Kevin L, Huang Jinzhou, Hitosugi Taro, Dai Haiming, Deng Min, Mutter Robert W, Lou Zhenkun
Аннотация
Okazaki fragment maturation requires efficient removal of RNA primers to form a continuous lagging strand, yet how mismatched primers introduced by error-prone primase are corrected remains unresolved. Here, we show that physiological levels of reactive oxygen species (ROS) initiate a redox-dependent mechanism that drives ADAR1-mediated adenosine-to-inosine (A-to-I) editing. Oxidation triggers ADAR1 dimerization at replication forks, enhancing RNA editing of mismatched primers-particularly those caused by ATP misincorporation on d(T+C)-rich centromeric DNA. This A-to-I editing step facilitates more efficient RNA primer degradation by RNase H2, thereby ensuring proper Okazaki fragment maturation. Disruption of ADAR1 oxidation results in increased unligated Okazaki fragments, single-stranded gaps and double-strand breaks, most prominently at centromeres. These findings reveal a role for ROS in safeguarding lagging-strand synthesis by coupling ADAR1 oxidation-induced A-to-I RNA editing to replication fork stability.