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

文献类型：期刊论文

作者Chen, Bin1,9; Sun, Guangchao2; Kloeber, Jake A.3,9; Xiao, Huaping1; Ouyang, Yaobin9; Zhao, Fei9; Li, Ya9; Xu, Shilin4; Dragojevic, Sonja1; Wu, Zheming1
刊名NATURE STRUCTURAL & MOLECULAR BIOLOGY
出版日期2026-01-08
页码35
ISSN号1545-9993
DOI10.1038/s41594-025-01736-w
通讯作者Deng, Min(dengmin@cicams.ac.cn) ; Mutter, Robert W.(Mutter.Robert@mayo.edu) ; Lou, Zhenkun(Lou.Zhenkun@mayo.edu)
英文摘要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.
WOS关键词TYPE-2 RNASE-H ; PRIMER REMOVAL ; RESIDUES ; PROTEIN
资助项目Mayo Foundation ; National Institutes of Health[R01CA264600] ; National Institutes of Health[R01CA285345] ; National Institutes of Health[R01CA272602] ; National Institutes of Health[R01CA261932] ; National Institutes of Health[P30CA015083] ; National Institutes of Health[T32GM65841] ; Mayo Clinic Office of Core Shared Services ; Mayo Clinic Comprehensive Cancer Center Grant[P30CA015083]
WOS研究方向Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
语种英语
WOS记录号WOS:001656581000001
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/322557]  
专题中国科学院上海药物研究所
通讯作者Deng, Min; Mutter, Robert W.; Lou, Zhenkun
作者单位1.Mayo Clin, Dept Radiat Oncol, Rochester, MN 55905 USA
2.Sichuan Agr Univ, Maize Res Inst, Chengdu, Peoples R China
3.Mayo Clin, Med Scientist Training Program, Rochester, MN USA
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai, Peoples R China
5.Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Mol Oncol, Natl Canc Ctr, Natl Clin Res Ctr Canc, Beijing, Peoples R China
6.Chinese Acad Med Sci & Peking Union Med Coll, Natl Canc Ctr, Natl Clin Res Ctr Canc, Dept Radiat Oncol, Beijing, Peoples R China
7.Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Beijing, Peoples R China
8.Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA
9.Mayo Clin, Dept Oncol, Rochester, MN 55905 USA
推荐引用方式
GB/T 7714		 Chen, Bin,Sun, Guangchao,Kloeber, Jake A.,et al. Redox-driven ADAR1 activation promotes Okazaki fragment maturation and DNA replication integrity[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY,2026:35.
APA Chen, Bin.,Sun, Guangchao.,Kloeber, Jake A..,Xiao, Huaping.,Ouyang, Yaobin.,...&Lou, Zhenkun.(2026).Redox-driven ADAR1 activation promotes Okazaki fragment maturation and DNA replication integrity.NATURE STRUCTURAL & MOLECULAR BIOLOGY,35.
MLA Chen, Bin,et al."Redox-driven ADAR1 activation promotes Okazaki fragment maturation and DNA replication integrity".NATURE STRUCTURAL & MOLECULAR BIOLOGY (2026):35.

入库方式： OAI收割

来源：上海药物研究所

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