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<p>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.</p>

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Redox-driven ADAR1 activation promotes Okazaki fragment maturation and DNA replication integrity

  • 期刊论文

  • 发表日期：

    2026年1月8日

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  • Bin Chen,
  • Guangchao Sun,
  • Jake A. Kloeber,
  • Huaping Xiao,
  • Yaobin Ouyang,
  • Fei Zhao,
  • Ya Li,
  • Shilin Xu,
  • Sonja Dragojevic,
  • Zheming Wu,
  • Shouhai Zhu,
  • Yiqun Han,
  • Ping Yin,
  • Xinyi Tu,
  • Hongran Qin,
  • Xiang Zhou,
  • Kuntian Luo,
  • Kevin L. Peterson,
  • Jinzhou Huang,
  • Taro Hitosugi,
  • Haiming Dai,
  • Min Deng,
  • Robert W. Mutter,
  • Zhenkun Lou

摘要

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.