2. Academic Validation
  3. Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation

Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation

  • Cell. 2013 Dec 19;155(7):1545-55. doi: 10.1016/j.cell.2013.11.020.
Lulu Hu 1,  Ze Li 2,  Jingdong Cheng 2,  Qinhui Rao 2,  Wei Gong 2,  Mengjie Liu 2,  Yujiang Geno Shi 3,  Jiayu Zhu 2,  Ping Wang 2,  Yanhui Xu 4
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center, Department of Oncology and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 2 Fudan University Shanghai Cancer Center, Department of Oncology and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
  • 3 Fudan University Shanghai Cancer Center, Department of Oncology and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Department of Biological Chemistry & Molecular Pharmacology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 4 Fudan University Shanghai Cancer Center, Department of Oncology and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China. Electronic address: [email protected].
PMID: 24315485 DOI: 10.1016/j.cell.2013.11.020
Abstract

TET proteins oxidize 5-methylcytosine (5mC) on DNA and play important roles in various biological processes. Mutations of TET2 are frequently observed in myeloid malignance. Here, we present the crystal structure of human TET2 bound to methylated DNA at 2.02 Å resolution. The structure shows that two zinc fingers bring the Cys-rich and DSBH domains together to form a compact catalytic domain. The Cys-rich domain stabilizes the DNA above the DSBH core. TET2 specifically recognizes CpG dinucleotide and shows substrate preference for 5mC in a CpG context. 5mC is inserted into the catalytic cavity with the methyl group orientated to catalytic Fe(II) for reaction. The methyl group is not involved in TET2-DNA contacts so that the catalytic cavity allows TET2 to accommodate 5mC derivatives for further oxidation. Mutations of Fe(II)/NOG-chelating, DNA-interacting, and zinc-chelating residues are frequently observed in human cancers. Our studies provide a structural basis for understanding the mechanisms of TET-mediated 5mC oxidation.

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