2. Academic Validation
  3. m6A demethylation of cytidine deaminase APOBEC3B mRNA orchestrates arsenic-induced mutagenesis

m6A demethylation of cytidine deaminase APOBEC3B mRNA orchestrates arsenic-induced mutagenesis

  • J Biol Chem. 2022 Feb;298(2):101563. doi: 10.1016/j.jbc.2022.101563.
Ming Gao 1,  Zijuan Qi 2,  Wenya Feng 1,  Hongyang Huang 3,  Zhijie Xu 4,  Zheng Dong 1,  Ming Xu 1,  Jinxiang Han 2,  Jake A Kloeber 5,  Jinzhou Huang 6,  Zhenkun Lou 7,  Sijin Liu 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, China.
  • 2 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, Shandong, China.
  • 3 Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 4 Department of Pathology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5 Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA; Mayo Clinic Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota, USA.
  • 6 Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: huang.jinzhou@mayo.edu.
  • 7 Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: lou.zhenkun@mayo.edu.
  • 8 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, China. Electronic address: sjliu@rcees.ac.cn.
PMID: 34998823 DOI: 10.1016/j.jbc.2022.101563
Abstract

The cytidine deaminase APOBEC3B (A3B) is an endogenous inducer of somatic mutations and causes chromosomal instability by converting cytosine to uracil in single-stranded DNA. Therefore, identification of factors and mechanisms that mediate A3B expression will be helpful for developing therapeutic approaches to decrease DNA mutagenesis. Arsenic (As) is one well-known mutagen and carcinogen, but the mechanisms by which it induces mutations have not been fully elucidated. Herein, we show that A3B is upregulated and required for As-induced DNA damage and mutagenesis. We found that As treatment causes a decrease of N6-methyladenosine (m6A) modification near the stop codon of A3B, consequently increasing the stability of A3B mRNA. We further reveal that the demethylase FTO is responsible for As-reduced m6A modification of A3B, leading to increased A3B expression and DNA mutation rates in a manner dependent on the m6A reader YTHDF2. Our in vivo data also confirm that A3B is a downstream target of FTO in As-exposed lung tissues. In addition, FTO protein is highly expressed and positively correlates with the protein levels of A3B in tumor samples from human non-small cell lung Cancer patients. These findings indicate a previously unrecognized role of A3B in As-triggered somatic mutation and might open new avenues to reduce DNA mutagenesis by targeting the FTO/m6A axis.

Keywords

APOBEC3B; FTO; arsenic; m6A modification; mutagenesis.

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