2. Academic Validation
  3. N6-Deoxyadenosine Methylation in Mammalian Mitochondrial DNA

N6-Deoxyadenosine Methylation in Mammalian Mitochondrial DNA

  • Mol Cell. 2020 May 7;78(3):382-395.e8. doi: 10.1016/j.molcel.2020.02.018.
Ziyang Hao 1,  Tong Wu 1,  Xiaolong Cui 1,  Pingping Zhu 2,  Caiping Tan 3,  Xiaoyang Dou 1,  Kai-Wen Hsu 4,  Yueh-Te Lin 4,  Pei-Hua Peng 4,  Li-Sheng Zhang 1,  Yawei Gao 5,  Lulu Hu 1,  Hui-Lung Sun 1,  Allen Zhu 1,  Jianzhao Liu 1,  Kou-Juey Wu 4,  Chuan He 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
  • 2 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; School of Life Science, Zhengzhou University, Zhengzhou 450001, China.
  • 3 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
  • 4 Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.
  • 5 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 6 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Electronic address: [email protected].
PMID: 32183942 DOI: 10.1016/j.molcel.2020.02.018
Abstract

N6-Methyldeoxyadenosine (6mA) has recently been shown to exist and play regulatory roles in eukaryotic genomic DNA (gDNA). However, the biological functions of 6mA in mammals have yet to be adequately explored, largely due to its low abundance in most mammalian genomes. Here, we report that mammalian mitochondrial DNA (mtDNA) is enriched for 6mA. The level of 6mA in HepG2 mtDNA is at least 1,300-fold higher than that in gDNA under normal growth conditions, corresponding to approximately four 6mA modifications on each mtDNA molecule. METTL4, a putative mammalian methyltransferase, can mediate mtDNA 6mA methylation, which contributes to attenuated mtDNA transcription and a reduced mtDNA copy number. Mechanistically, the presence of 6mA could repress DNA binding and bending by mitochondrial transcription factor (TFAM). Under hypoxia, the 6mA level in mtDNA could be further elevated, suggesting regulatory roles for 6mA in mitochondrial stress response. Our study reveals DNA 6mA as a regulatory mark in mammalian mtDNA.

Keywords

METTL4; N(6)-methyldeoxyadenosine (6mA); TFAM; methyltransferase; mitochondrial DNA methylation; mitochondrial replication; mitochondrial transcription regulation.

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