J Cancer 2021; 12(23):7041-7051. doi:10.7150/jca.64061 This issue

Research Paper

N6-methyladenosine regulates ATM expression and downstream signaling

Xiaoyue Zhang1,2,3*, Peishan Liu2,3*, Xiang Zheng2,3,4, Jia Wang2,3,5, Qiu Peng1,2,3, Zhengshuo Li2,3, Lingyu Wei2,3,5, Can Liu2,3, Yangge Wu2,3, Yuqing Wen2,3, Qun Yan6✉, Jian Ma1,2,3✉

1. Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
2. Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China.
3. Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Hunan Key Laboratory of Cancer Metabolism, Changsha, China.
4. Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
5. Department of Immunology, Department of Pathology, Heping Hospital, Changzhi Medical College, Changzhi, Shanxi, China.
6. Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China.
*These authors contributed equally to this work.

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Citation:
Zhang X, Liu P, Zheng X, Wang J, Peng Q, Li Z, Wei L, Liu C, Wu Y, Wen Y, Yan Q, Ma J. N6-methyladenosine regulates ATM expression and downstream signaling. J Cancer 2021; 12(23):7041-7051. doi:10.7150/jca.64061. Available from https://www.jcancer.org/v12p7041.htm

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Abstract

Graphic abstract

N6-methyladenosine (m6A) is the most abundant modification in eukaryotic mRNAs, which plays an important role in regulating multiple biological processes. ATM is a major protein kinase that regulates the DNA damage response. Here, we identified that ATM is a m6A-modificated gene. METTL3 (a m6A “writer”) and FTO (a m6A “eraser”) oppositely regulated ATM expression and its downstream signaling. Mechanically, m6A “readers” YTHDFs and eIF3A suppressed ATM expression in the post-transcriptional levels. We also revealed the oncogenic potential of METTL3 and YTHDF1 related to ATM modulation. This is the first report that ATM, a master in the DNA damage response, is modified by m6A epigenetic modification, and METTL3 disrupts the ATM stability via m6A modification, thereby affecting the DNA-damage response.

Keywords: m6A modification, ATM, DNA damage response, METTL3, YTHDF1