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Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA

Nature Chemical Biology volume 8, pages 328–330 (2012)Cite this article

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Abstract

Human thymine DNA glycosylase (hTDG) efficiently excises 5-carboxylcytosine (5caC), a key oxidation product of 5-methylcytosine in genomic DNA, in a recently discovered cytosine demethylation pathway. We present here the crystal structures of the hTDG catalytic domain in complex with duplex DNA containing either 5caC or a fluorinated analog. These structures, together with biochemical and computational analyses, reveal that 5caC is specifically recognized in the active site of hTDG, supporting the role of TDG in mammalian 5-methylcytosine demethylation.

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Figure 1: EMSA of hTDGcat(N140A) with 23-base-pair dsDNA containing G·5fC and G·5caC pairs.
Figure 2: Schematic diagram of the hTDGcat(N140A)–A·5caC complex structure.

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Acknowledgements

This study was supported by the US National Institutes of Health (GM071440 to C.H.), the 973 grant (2009CB918502 to H.J.), the Chinese Academy of Sciences (XDA01040305 to C.L.) and beamlines 23ID-B (General Medicine and Cancer Institutes Collaborative Access Team) and 24ID-E (Northeastern Collaborative Access Team) at the Advanced Photon Source at Argonne National Laboratory. We thank X. Yang from the University of Chicago and D. Borek from the University of Texas Southwestern Medical Center for structure data processing and discussion.

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Authors and Affiliations

  1. Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois, USA

    Liang Zhang, Xingyu Lu, Haihua Liang, Qing Dai & Chuan He

  2. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Junyan Lu, Cheng Luo & Hualiang Jiang

  3. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Guo-Liang Xu

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  1. Liang Zhang
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Contributions

L.Z., X.L. and C.H. conceived the original idea. L.Z., X.L., H.L. and C.H. designed the experiments with help from G.-L.X. and H.J.; the 5hmU and β-F-5caC phosphoramidites were synthesized by Q.D.; biochemistry assays and structural studies were performed by L.Z., X.L. and H.L.; the computational stimulation was performed by J.L., C.L. and H.J.; and L.Z., X.L., J.L, C.L. and C.H. wrote the paper. All authors discussed results and commented on the manuscript.

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Correspondence to Chuan He.

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Zhang, L., Lu, X., Lu, J. et al. Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol 8, 328–330 (2012). https://doi.org/10.1038/nchembio.914

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