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Structural insight into substrate preference for TET-mediated oxidation.

DNA methylation is an important epigenetic modification (1-3). Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (4-8). Here we show... Full description

Journal Title: Nature November 5, 2015, Vol.527(7576), pp.118-122
Main Author: Hu, Lulu
Other Authors: Lu, Junyan , Cheng, Jingdong , Rao, Qinhui , Li, Ze , Hou, Haifeng , Lou, Zhiyong , Zhang, Lei , Li, Wei , Gong, Wei , Liu, Mengjie , Sun, Chang , Yin, Xiaotong , Li, Jie , Tan, Xiangshi , Wang, Pengcheng , Wang, Yinsheng , Fang, Dong , Cui, Qiang , Yang
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1476-4687 ; DOI: 10.1038/nature15713
Link: http://search.proquest.com/docview/1731791219/?pq-origsite=primo
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title: Structural insight into substrate preference for TET-mediated oxidation.
format: Article
creator:
  • Hu, Lulu
  • Lu, Junyan
  • Cheng, Jingdong
  • Rao, Qinhui
  • Li, Ze
  • Hou, Haifeng
  • Lou, Zhiyong
  • Zhang, Lei
  • Li, Wei
  • Gong, Wei
  • Liu, Mengjie
  • Sun, Chang
  • Yin, Xiaotong
  • Li, Jie
  • Tan, Xiangshi
  • Wang, Pengcheng
  • Wang, Yinsheng
  • Fang, Dong
  • Cui, Qiang
  • Yang
subjects:
  • 5-Methylcytosine–Metabolism
  • Biocatalysis–Analogs & Derivatives
  • Catalytic Domain–Metabolism
  • Crystallography, X-Ray–Chemistry
  • Cytosine–Metabolism
  • DNA–Chemistry
  • DNA Methylation–Metabolism
  • DNA-Binding Proteins–Chemistry
  • Humans–Metabolism
  • Hydrogen Bonding–Metabolism
  • Mixed Function Oxygenases–Metabolism
  • Models, Molecular–Metabolism
  • Oxidation-Reduction–Metabolism
  • Protein Binding–Metabolism
  • Proto-Oncogene Proteins–Metabolism
  • Substrate Specificity–Metabolism
  • 5-Formylcytosine
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
ispartof: Nature, November 5, 2015, Vol.527(7576), pp.118-122
description: DNA methylation is an important epigenetic modification (1-3). Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (4-8). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET25fC-DNA complexes at 1.80 [Angstrom] and 1.97 [Angstrom] resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure (9), and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.
language: eng
source:
identifier: E-ISSN: 1476-4687 ; DOI: 10.1038/nature15713
fulltext: fulltext
issn:
  • 14764687
  • 1476-4687
url: Link


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titleStructural insight into substrate preference for TET-mediated oxidation.
creatorHu, Lulu ; Lu, Junyan ; Cheng, Jingdong ; Rao, Qinhui ; Li, Ze ; Hou, Haifeng ; Lou, Zhiyong ; Zhang, Lei ; Li, Wei ; Gong, Wei ; Liu, Mengjie ; Sun, Chang ; Yin, Xiaotong ; Li, Jie ; Tan, Xiangshi ; Wang, Pengcheng ; Wang, Yinsheng ; Fang, Dong ; Cui, Qiang ; Yang
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ispartofNature, November 5, 2015, Vol.527(7576), pp.118-122
identifierE-ISSN: 1476-4687 ; DOI: 10.1038/nature15713
subject5-Methylcytosine–Metabolism ; Biocatalysis–Analogs & Derivatives ; Catalytic Domain–Metabolism ; Crystallography, X-Ray–Chemistry ; Cytosine–Metabolism ; DNA–Chemistry ; DNA Methylation–Metabolism ; DNA-Binding Proteins–Chemistry ; Humans–Metabolism ; Hydrogen Bonding–Metabolism ; Mixed Function Oxygenases–Metabolism ; Models, Molecular–Metabolism ; Oxidation-Reduction–Metabolism ; Protein Binding–Metabolism ; Proto-Oncogene Proteins–Metabolism ; Substrate Specificity–Metabolism ; 5-Formylcytosine ; DNA-Binding Proteins ; Proto-Oncogene Proteins
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descriptionDNA methylation is an important epigenetic modification (1-3). Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (4-8). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET25fC-DNA complexes at 1.80 [Angstrom] and 1.97 [Angstrom] resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure (9), and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.
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titleStructural insight into substrate preference for TET-mediated oxidation.
authorHu, Lulu ; Lu, Junyan ; Cheng, Jingdong ; Rao, Qinhui ; Li, Ze ; Hou, Haifeng ; Lou, Zhiyong ; Zhang, Lei ; Li, Wei ; Gong, Wei ; Liu, Mengjie ; Sun, Chang ; Yin, Xiaotong ; Li, Jie ; Tan, Xiangshi ; Wang, Pengcheng ; Wang, Yinsheng ; Fang, Dong ; Cui, Qiang ; Yang
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5DNA–Chemistry
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10Mixed Function Oxygenases–Metabolism
11Models, Molecular–Metabolism
12Oxidation-Reduction–Metabolism
13Protein Binding–Metabolism
14Proto-Oncogene Proteins–Metabolism
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165-Formylcytosine
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