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Molecular mechanism for vitamin C-derived C5-glyceryl-methylcytosine DNA modification catalyzed by algal TET homologue CMD1

Author

Listed:
  • Wenjing Li

    (University of Chinese Academy of Sciences)

  • Tianlong Zhang

    (University of Chinese Academy of Sciences)

  • Mingliang Sun

    (University of Chinese Academy of Sciences)

  • Yu Shi

    (University of Chinese Academy of Sciences
    ShanghaiTech University)

  • Xiao-Jie Zhang

    (University of Chinese Academy of Sciences)

  • Guo-Liang Xu

    (University of Chinese Academy of Sciences)

  • Jianping Ding

    (University of Chinese Academy of Sciences
    ShanghaiTech University
    University of Chinese Academy of Sciences)

Abstract

C5-glyceryl-methylcytosine (5gmC) is a novel DNA modification catalyzed by algal TET homologue CMD1 using vitamin C (VC) as co-substrate. Here, we report the structures of CMD1 in apo form and in complexes with VC or/and dsDNA. CMD1 exhibits comparable binding affinities for DNAs of different lengths, structures, and 5mC levels, and displays a moderate substrate preference for 5mCpG-containing DNA. CMD1 adopts the typical DSBH fold of Fe2+/2-OG-dependent dioxygenases. The lactone form of VC binds to the active site and mono-coordinates the Fe2+ in a manner different from 2-OG. The dsDNA binds to a positively charged cleft of CMD1 and the 5mC/C is inserted into the active site and recognized by CMD1 in a similar manner as the TET proteins. The functions of key residues are validated by mutagenesis and activity assay. Our structural and biochemical data together reveal the molecular mechanism for the VC-derived 5gmC DNA modification by CMD1.

Suggested Citation

  • Wenjing Li & Tianlong Zhang & Mingliang Sun & Yu Shi & Xiao-Jie Zhang & Guo-Liang Xu & Jianping Ding, 2021. "Molecular mechanism for vitamin C-derived C5-glyceryl-methylcytosine DNA modification catalyzed by algal TET homologue CMD1," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21061-2
    DOI: 10.1038/s41467-021-21061-2
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